Viral polymerase inhibitors

ABSTRACT

An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula I:  
                 
 
     wherein wherein A, B, R 2 , R 3 , L, M 1 , M 2 , M 3 , M 4 , Y 1 , Y 0 , Z and Sp are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.

RELATED APPLICATIONS

[0001] Benefit of U.S. Provisional Application, Serial No. 60/441,871,filed on Jan. 22, 2003, is hereby claimed and said application is hereinincorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

[0002] The invention relates to inhibitors of RNA dependent RNApolymerases, particularly those viral polymerases within theFlaviviridae family, more particularly to HCV polymerase.

BACKGROUND OF THE INVENTION

[0003] About 30,000 new cases of hepatitis C virus (HCV) infection areestimated to occur in the United States each year (Kolykhalov, A. A.;Mihalik, K.; Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74:2046-2051). HCV is not easily cleared by the hosts' immunologicaldefences; as many as 85% of the people infected with HCV becomechronically infected. Many of these persistent infections result inchronic liver disease, including cirrhosis and hepatocellular carcinoma(Hoofnagle, J. H.; 1997; Hepatology 26: 15S-20S*). There are anestimated 170 million HCV carriers world-wide, and HCV-associatedend-stage liver disease is now the leading cause of livertransplantation. In the United States alone, hepatitis C is responsiblefor 8,000 to 10,000 deaths annually. Without effective intervention, thenumber is expected to triple in the next 10 to 20 years. There is novaccine to prevent HCV infection. Prolonged treatment of chronicallyinfected patients with interferon or interferon and ribavirin is theonly currently approved therapy, but it achieves a sustained response infewer than 50% of cases (Lindsay, K. L.; 1997; Hepatology 26: 71S-77S*,and Reichard, O.; Schvarcz, R.; Weiland, O.; 1997 Hepatology26:108S-111S*).

[0004] HCV belongs to the family Flaviviridae, genus hepacivirus, whichcomprises three genera of small enveloped positive-strand RNA viruses(Rice, C. M.; 1996; “Flaviviridae: the viruses and their replication”;pp. 931-960 in Fields Virology; Fields, B. N.; Knipe, D. M.; Howley, P.M. (eds.); Lippincott-Raven Publishers, Philadelphia Pa.*). The 9.6 kbgenome of HCV consists of a long open reading frame (ORF) flanked by 5′and 3′ non-translated regions (NTR's). The HCV 5′ NTR is 341 nucleotidesin length and functions as an internal ribosome entry site forcap-independent translation initiation (Lemon, S. H.; Honda, M.; 1997;Semin. Virol. 8: 274-288). The HCV polyprotein is cleaved co- andpost-translationally into at least 10 individual polypeptides (Reed, K.E.; Rice, C. M.; 1999; Curr. Top. Microbiol. Immunol. 242: 55-84*). Thestructural proteins result from signal peptidases in the N-terminalportion of the polyprotein. Two viral proteases mediate downstreamcleavages to produce non-structural (NS) proteins that function ascomponents of the HCV RNA replicase. The NS2-3 protease spans theC-terminal half of the NS2 and the N-terminal one-third of NS3 andcatalyses cis cleavage of the NS2/3 site. The same portion of NS3 alsoencodes the catalytic domain of the NS3-4A serine protease that cleavesat four downstream sites. The C-terminal two-thirds of NS3 is highlyconserved amongst HCV isolates, with RNA-binding, RNA-stimulated NTPase,and RNA unwinding activities. Although NS4B and the NS5A phosphoproteinare also likely components of the replicase, their specific roles areunknown. The C-terminal polyprotein cleavage product, NS5B, is theelongation subunit of the HCV replicase possessing RNA-dependent RNApolymerase (RdRp) activity (Behrens, S. E.; Tomei, L.; DeFrancesco, R.;1996; EMBO J. 15: 12-22*; and Lohmann, V.; Korner, F.; Herian, U.;Bartenschlager, R.; 1997; J. Virol. 71: 8416-8428*). It has beenrecently demonstrated that mutations destroying NS5B activity abolishinfectivity of RNA in a chimp model (Kolykhalov, A. A.; Mihalik, K.;Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74: 2046-2051*).

[0005] The development of new and specific anti-HCV treatments is a highpriority, and virus-specific functions essential for replication are themost attractive targets for drug development. The absence of RNAdependent RNA polymerases in mammals, and the fact that this enzymeappears to be essential to viral replication, would suggest that theNS5B polymerase is an ideal target for anti-HCV therapeutics. WO00/06529, WO 00/13708, WO 00/10573, WO 00/18231, WO 01/47883, WO01/85172 and WO 02/04425 report inhibitors of NS5B proposed fortreatment of HCV.

SUMMARY OF THE INVENTION

[0006] It is therefore an object of the invention to provide a novelseries of compounds having good to very good inhibitory activity againstHCV polymerase.

[0007] Further objects of this invention arise for the one skilled inthe art from the following description and the examples.

[0008] In a first aspect of the invention, there is provided an isomer,enantiomer, diastereoisomer or tautomer of a compound, represented byformula I:

[0009] wherein:

[0010] either A or B is N and the other B or A is C, wherein - - -between two C-atoms represents a double bond and - - - between a C-atomand a N-atom represents a single bond,

[0011] the group —C(═Y¹)-Z is covalently linked to either M² or M³,

[0012] M¹ is CR^(4a),

[0013] M² or M³, when not linked to —C(═Y¹)-Z, is CR⁵,

[0014] M⁴ is CR^(4b),

[0015] and in addition one or two of the groups selected from M¹, M², M³and M⁴ may also be N, with the proviso that the group M² or M³ to which—C(═Y′)-Z is linked is an C-atom,

[0016] Sp is a spacer group selected from —(CR⁵¹R⁵²)_(k1)—, wherein

[0017] k1 is 1, 2 or 3;

[0018] R⁵¹, R⁵² are independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, or

[0019] R⁵¹ and R⁵² are covalently bonded together and to the carbon-atomto which they are attached to form a 3, 4, 5, 6 or 7-membered saturatedor 5, 6 or 7-membered unsaturated cyclic system whereby the 5, 6 or7-membered saturated or unsaturated cyclic system optionally contains 1to 3 heteroatoms selected from N, O or S;

[0020] said alkyl, cycloalkyl, alkyl-cycloalkyl or cyclic system beingoptionally substituted by halogen, hydroxy, (C₁₋₆)alkoxy, cyano, amino,—NH(C₁₋₄-alkyl) and/or —N(C₁₋₄-alkyl)₂;

[0021] Y⁰ is O, S, NR¹¹ or CR¹²R¹³, wherein

[0022] R¹¹, R¹², R¹³ are each independently defined as R^(O);

[0023] R¹³ may also be COOR^(O) or SO₂R^(C);

[0024] wherein R^(C) and each R^(O) is optionally substituted with R¹⁵⁰;

[0025] or both R¹² and R¹³ are covalently bonded together and to thecarbon-atom to which they are attached to form a 3, 4, 5, 6 or7-membered saturated or 5, 6 or 7-membered unsaturated cyclic systemwhereby the 5, 6 or 7-membered saturated or unsaturated cyclic systemmay contain 1 to 3 heteroatoms selected from N, O or S; said cyclicsystems being optionally substituted with R¹⁵⁰;

[0026] L is C₁₋₆alkyl, (C₃₋₆)cycloalkyl, C₁₋₆alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, aryl, (C₁₋₆alkyl)aryl, Het, (C₁₋₆)alkyl-Het, all of whichbeing optionally substituted with R⁶⁰;

[0027] or Y⁰ and L are covalently bonded to form a 5, 6, 7 or 8-memberedmono- or a 8, 9, 10 or 11 -membered bicyclic group which is optionallyunsaturated or aromatic and which optionally contains 1, 2 or 3heteroatoms selected from N, O and S, wherein the mono- or bicyclicgroup is optionally substituted with R⁶⁰;

[0028] or if Y⁰ is CR¹²R¹³, then L may also be H;

[0029] or if Y⁰ is O, then L may also be OR^(C),

[0030] wherein R^(C) is optionally substituted with R⁶⁰;

[0031] or if Y⁰ is O, S or NR¹¹, then L may also be N(R^(N2))R^(N1),NR^(N3)—N(R^(N2))R^(N1), NR^(N3)—NR^(N2)CO—R^(C),NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1), NR^(N2)—SO₂—R^(C), NR^(N2)—CO—R^(C),NR^(N3)—CO—N(R^(N2))R^(N1) or N(R^(N1))OR^(O);

[0032] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1), R^(N2) and/or R^(N3), and R^(C) and R^(O) being optionallysubstituted with R⁶⁰;

[0033] or if Y⁰ is O or S, then L may also be OR^(6a) orN(R^(5a))R^(6a), wherein R^(5a) is defined as R^(N2),

[0034] and wherein R^(6a) is:

[0035] or R^(6a) is:

[0036] wherein R^(7a) and R^(8a) are each independently defined asR^(O), COOR^(O) or CON(R^(N2))R^(N1), wherein said R^(O) is optionallysubstituted with R⁶⁰; or R^(7a) and R^(8a) are covalently bondedtogether to form a (C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocyclehaving from 1 to 3 heteroatom selected from O, N, and S; and when L isN(R^(5a))R^(6a), either of R^(7a) or R^(8a) may be covalently bonded toR^(5a) to form a nitrogen-containing 5-or 6-membered heterocycle,wherein said cycloalkyl or heterocycle being optionally substituted byR¹⁵⁰; and

[0037] W¹ is selected from

[0038] a) a single bond;

[0039] b) —CH₂—;

[0040] c) —CH₂—CH₂—; and

[0041] d) —CH═CH—;

[0042] wherein the alkylene and alkenylene groups according to b), c)and d) may be substituted with (C₁₋₃) alkyl;

[0043] Y² is O or S;

[0044] R^(9a) is defined as R^(O), wherein said R^(O) is optionallysubstituted with R⁶⁰; or

[0045] R^(9a) is covalently bonded to either of R^(7a) or R^(8a) to forma 5- or 6-membered heterocycle;

[0046] Q¹ is aryl, Het, (C₁₋₆) alkyl-aryl, (C₁₋₆) alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which being optionallysubstituted with R⁶⁰;

[0047] Y¹ is O, S or NR¹⁴, wherein R¹⁴ is H or (C₁₋₆)alkyl;

[0048] Z is defined as

[0049] a) OR^(O);

[0050] b) SO₂R^(C);

[0051] c) N(R^(N2))R^(N1);

[0052] d) NR^(N3)—N(R^(N2))R^(N1);

[0053] e) NR^(N3)—NR^(N2)—CO—R^(C);

[0054] f) NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1);

[0055] g) NR^(N2)—SO₂—R^(C) or

[0056] h) NR^(N3)—SO₂—N(R^(N2))R^(N1);

[0057] i) NR^(N2)—CO—R^(C);

[0058] j) COOR^(O);

[0059] k) N(R^(N1))OR^(O);

[0060] wherein R^(O) and R^(C) are optionally substituted with R⁶⁰; and

[0061] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1), R^(N2), and/or R^(N3), being optionally substituted with R⁶⁰;

[0062] or Z is OR^(6b) or N(R^(5b))R^(6b) wherein R^(5b) is defined asR^(N2) and R^(6b) is:

[0063] or R^(6b) is:

[0064] wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a),R^(8a), Y², R^(9a), W¹ respectively; and

[0065] Q² is aryl, Het, (C₁₋₆) alkyl-aryl, (C₁₋₆) alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which being optionallysubstituted with R⁶⁰ or Q² is R¹⁶⁰

[0066] or Q² is selected from the group consisting of O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of whichbeing optionally substituted with R¹⁶⁰; and

[0067] R² is selected from: halogen or R²¹, wherein R²¹ is aryl or Het,said R²¹ is optionally substituted with R¹⁵⁰;

[0068] R³ is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl,(C₁₋₃)alkyl-(C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl,(C₁₋₃)alkyl-(C₆₋₁₀)bicycloalkyl, (C₆₋₁₀)bicycloalkenyl,(C₁₋₃)alkyl-(C₆₋₁₀)bicycloalkenyl, HCy or (C₁₋₃)alkyl-HCy,

[0069] wherein HCy is a saturated or unsaturated 4 to 7-memberedheterocyclic group with 1 to 3 heteroatoms selected from O, S and N;

[0070] said alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl,bicycloalkenyl, HCy and alkyl-HCy being optionally substituted with from1 to 4 substituents selected from: a) halogen;

[0071] b) (C₁₋₆)alkyl optionally substituted with:

[0072] 1 to 3 substituents selected from halogen;

[0073] OR³¹ or SR³¹ wherein R³¹ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or

[0074] N(R³²)₂ wherein each R³² is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³² arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle;

[0075] c) OR³³ or SR³³ wherein R³³ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkylor (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl;

[0076] d) N(R³⁵)₂ wherein each R³⁵ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³⁵ arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle;

[0077] R^(4a), R^(4b), R⁵ each are independently H or defined as R¹⁵⁰;

[0078] R⁶⁰ is each defined as 1 to 4 substituents independently selectedfrom:

[0079] 1 to 3 substituents selected from halogen;

[0080] one of each substituent selected from: OPO₃H, NO₂, cyano, azido,C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl, SO₃H; and

[0081] 1 to 3 substituents selected from:

[0082] a) (C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyloptionally containing 1 or 2 heteroatoms selected from N, O and S;(C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, all of whichoptionally being substituted with R¹⁵⁰;

[0083] b) OR^(O);

[0084] c) OC(O)R^(O);

[0085] d) SR^(O), SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C),CONR^(N3)SO₂N(R^(N2))R^(N1), or CONR^(N2)SO₂R^(C);

[0086] e) N(R^(N2))R^(N1, N(R) ^(N2))COOR^(C), N(R^(N2))SO₂R^(C) orN(R^(N1 )R) ^(O);

[0087] f) N(R^(N2))COR^(C);

[0088] g) N(R^(N3))CON(R^(N2))R^(N1);

[0089] h) N(R^(N3))COCOR^(C), N(R^(N3))COCOOR^(O) orN(R^(N3))COCON(R^(N2))R^(N1);

[0090] i) COR^(O);

[0091] j) COOR^(O);

[0092] k) CON(R^(N2))R^(N1);

[0093] l) aryl, Het, (C₁₋₄alkyl)aryl or (C₁₋₄alkyl)Het, all of whichoptionally being substituted with R¹⁵⁰;

[0094] wherein said R^(N1), R^(C) and R^(O) are each independentlyoptionally substituted with R¹⁵⁰ as defined,

[0095] R¹⁵⁰ is each defined as 1 to 4 substituents independentlyselected from:

[0096] 1 to 3 substituents selected from halogen;

[0097] one of each substituent selected from: OPO₃H, NO₂, cyano, azido,C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl; and

[0098] 1 to 3 substituents selected from:

[0099] a) (C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyloptionally containing 1 or 2 heteroatoms selected from N, O and S;(C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, all of whichoptionally substituted with R¹⁶⁰;

[0100] b) OR^(O);

[0101] c) OC(O)R^(O);

[0102] d) SR^(O), SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C) orCON(R^(N2))SO₂R^(C);

[0103] e) N(R^(N2))R^(N1), N(R^(N2))COOR^(C), N(R^(N2))SO₂R^(C), orN(R^(N1))R^(O);

[0104] f) N(R^(N2))COR^(C);

[0105] g) N(R^(N3))CON(R^(N2))R^(N1);

[0106] h) N(R^(N3))COCOR^(C), N(R^(N3))COCOOR^(O),N(R^(N3))COCON(R^(N2))OH, N(R^(N3))COCON(R^(N2))OC₁₋₄-alkyl orN(R^(N3))COCON(R^(N2))R^(N1);

[0107] i) COR^(O);

[0108] j) COOR^(O);

[0109] k) tetrazole, triazole, CONR^(N3)—SO₂N(R^(N2))R^(N1); orCON(R^(N2))R^(N1);

[0110] wherein said R^(N1), R^(C) and/or R^(O) are optionallysubstituted with R¹⁶⁰ as defined;

[0111] R¹⁶⁰ is each defined as 1, 2 or 3 substituents independentlyselected from:

[0112] 1, 2 or 3 fluorine substituents; and

[0113] one of each substituent selected from tetrazole, triazole,chlorine, bromine, iodine, CN, nitro, C₁₋₄alkyl, CF₃, COOR¹⁶¹, SO₃H,SR¹⁶¹, SCF₃, SO₂R¹⁶³, OR¹⁶¹, OCF₃, N(R¹⁶²)₂, SO₂N(R¹⁶²)₂, NR¹⁶²SO₂R^(C),NR¹⁶²COR¹⁶², CON(R¹⁶²)₂, —NR¹⁶¹—CO—COOR¹⁶¹, —NR¹⁶¹—CO—CO(NR¹⁶²)₂,—CONR¹⁶¹SO₂R^(C), CONR¹⁶¹—SO₂N(R¹⁶²)₂ or —SO₂—NR¹⁶¹—COR^(C), whereinR¹⁶¹, R¹⁶³ and each R¹⁶² is independently (C₁₋₄)alkyl, (C₃₋₇)cycloalkylor (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; and

[0114] R¹⁶¹ and each R¹⁶² may each independently also be H; or both R¹⁶²are covalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle;

[0115] R^(O), R^(C) are independently defined as (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₄)alkyl-aryl and (C₁₋₄)alkyl-Het; and

[0116] R^(O) may also be H;

[0117] R^(N1) is independently selected from H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₄)alkyl-aryl, (C₁₋₄)alkyl-Het; or

[0118] R^(N2), R^(N3), R^(N4) are independently H, CH₃, (C₂₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; wherein said alkyl,cycloalkyl or alkylcycloalkyl is optionally substituted with hydroxy,halogen, carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, amino,—NH(C₁₋₄-alkyl) and/or —N(C₁₋₄-alkyl)₂; and wherein said CH₃ isoptionally substituted with halogen, carboxy or C₁₋₆alkoxycarbonyl; and

[0119] in the case

[0120] a) of a group N(R^(N2))R^(N1) the substituents R^(N2) and R^(N1);or

[0121] b) of a group NR^(N3)—N(R^(N2))R^(N1) the substituents R^(N3) andR^(N1), or R^(N2) and R^(N1);

[0122] may be covalently bonded together to form a 4-, 5-, 6- or7-membered saturated or unsaturated N-containing heterocycle or a 8-,9-, 10- or 11-membered N-containing heterobicycle each may haveadditionally from 1 to 3 heteroatoms selected from O, N, and S;

[0123] wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, or a 8-, 9-, 10- or11-membered heterobicycle having 1 to 5 heteroatoms selected from O, Nand S;

[0124] or a salt thereof.

[0125] Included within the scope of this invention are compounds of theformula (I) as described hereinbefore, to which a “detectable label”,“affinity tag” or “photoreactive group” is linked.

[0126] The compounds according to this invention generally show a goodto very good inhibitory activity against HCV polymerase. In particularcompounds according to this invention inhibit RNA synthesis by the RNAdependent RNA polymerase of HCV, especially of the enzyme NS5B encodedby HCV. A further advantage of compounds provided by this invention istheir low to very low or even non-significant activity against otherpolymerases.

[0127] In a second aspect of the invention, there is provided a use of acompound of formula I according to this invention, or a pharmaceuticallyacceptable salt thereof, as an HCV polymerase inhibitor.

[0128] In a third aspect of the invention, there is provided a use of acompound of the formula I according to this invention, or apharmaceutically acceptable salt thereof, as an inhibitor of RNAdependent RNA polymerase activity of the enzyme NS5B, encoded by HCV.

[0129] In a fourth aspect of the invention, there is provided a use of acompound of the formula I according to this invention, or apharmaceutically acceptable salt thereof, as an inhibitor of HCVreplication.

[0130] In a fifth aspect of the invention, there is provided a method oftreating or preventing HCV infection in a mammal, comprisingadministering to the mammal an effective amount of a compound of formulaI according to this invention, or a pharmaceutically acceptable saltthereof.

[0131] In a sixth aspect of the invention, there is provided a method oftreating or preventing HCV infection in a mammal, comprisingadministering to the mammal an effective amount of a compound of formulaI, or a pharmaceutically acceptable salt thereof in combination withanother antiviral agent.

[0132] In a seventh aspect of the invention, there is provided apharmaceutical composition for the treatment or prevention of HCVinfection, comprising an effective amount of a compound of formula Iaccording to this invention, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

[0133] According to a specific embodiment, the pharmaceuticalcompositions of this invention comprise a therapeutically effectiveamount of one or more antiviral agents. Examples of antiviral agentsinclude, ribavirin and amantadine.

[0134] According to a further specific embodiment, the pharmaceuticalcompositions of this invention comprise an other anti-HCV agent as anantiviral agent.

[0135] According to a more specific embodiment, the pharmaceuticalcompositions of this invention comprise an additional immunomodulatoryagent as an other anti-HCV agent. Examples of additionalimmunomodulatory agents include but are not limited to, α-, β-, δ- γ-,tau- and co-interferons.

[0136] According to another more specific embodiment, the pharmaceuticalcompositions of this invention comprise another inhibitor of HCVpolymerase as an other anti-HCV agent.

[0137] According to another more specific embodiment, the pharmaceuticalcompositions of this invention comprise an inhibitor of HCV NS3 proteaseas an other anti-HCV agent.

[0138] According to yet another more specific embodiment, thepharmaceutical compositions of this invention comprise an inhibitor ofanother target in the HCV life cycle as an other anti-HCV agent.Examples of such other targets are HCV helicase, HCV NS2/3 protease orHCV IRES.

[0139] In an eighth aspect of the invention, there is provided a use ofa compound of formula I according to this invention, or of apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment and/or the prevention of a Flaviviridaeviral infection, preferably an HCV infection.

[0140] In a ninth aspect of the invention, there is provided anintermediate compound represented by the formula 2(v) and 2′(v)

[0141] wherein Y⁰, L, Sp, R⁰ and R³ are defined as hereinbefore; and

[0142] X is Cl, Br or I.

[0143] Furthermore in a tenth aspect of this invention an intermediatecompound represented by the formula

[0144] wherein Y¹, Z, R², R³, R^(4a), R^(4b) and R⁵ are defined ashereinbefore;

[0145] not including compounds P1, P2, P3 and P4 of the followingformula

wherein Cpd. R² Z P1

—O—CH3 P2

—OH P3

—OH P4

—OH

[0146] In a eleventh aspect of the invention, there is provided a use ofthe intermediate compounds as defined above for the manufacture ofcompounds according to this invention.

[0147] A twelfth aspect of this invention is related to a process forproducing compounds of formula I.1

[0148] wherein Y⁰, L, Sp, R⁰, R² and R³ are defined as before,

[0149] comprising the reaction of an indole derivative of the formula2(iv)

[0150] wherein R⁰ and R³ are defined as hereinbefore and X is Cl, Br orI; according to one of the following methods a), b), c) or d):

[0151] 1.) cross-coupling of the indole derivative of the formula 2(iv)with an organometallic species such as, but not limited to

[0152] i) a stannane derivative of the formula R²—SnR′₃, wherein R² isdefined as hereinbefore and R′ is a C₁₋₈-alkyl or aryl group; or

[0153] ii) a boronic acid derivative R²—B(OH)₂ and R²—B(OR′)₂, whereinR² and R′ are defined as hereinbefore;

[0154] under transition metal catalysis to yield an indole derivative ofthe formula 2(vii)

[0155] wherein R⁰, R² and R³ are defined as hereinbefore;

[0156] 2.) the indole derivative of the formula 2(vii) is furtherprocessed by N-alkylation using the electrophilic reagent X-Sp-C(═Y⁰)-L,wherein X is a leaving group, like e.g. Cl, Br, I, mesylate, triflate,tosylate; and Sp, Y⁰ and L are as defined hereinbefore, in the presenceof a strong base, yielding the product of the formula I.1; or

[0157] b) 1.) halogen-metal exchange of the indole derivative of theformula 2(iv) using an alkyllithium reagent or lithium metal; and

[0158] 2.) trans-metallation of the reaction product yielded by theprevious step using:

[0159] i) a trialkyl tin halide;

[0160] ii) a trialkyl borate; or

[0161] iii) zinc chloride; and

[0162] 3.) cross-coupling of the reaction product yielded by theprevious step using R²—X, wherein R² is defined as hereinbefore and X isF, Cl, Br, I or triflate, under transition metal catalysis to yield anindole derivative of the formula 2(vii) as defined hereinbefore; and

[0163] 4.) the indole derivative of the formula 2(vii) is furtherprocessed by N-alkylation using the electrophilic reagent X-Sp-C(═Y⁰)-L,wherein X is a leaving group, like e.g. Cl, Br, I, mesylate, triflate,tosylate; and Sp, Y⁰ and L are as defined hereinbefore, in the presenceof a strong base, yielding the product of the formula I.1; or

[0164] c) 1.) N-alkylation of the indole derivative of the formula 2(iv)using the electrophilic reagent X-Sp-C(═Y⁰)-L, wherein X is a leavinggroup, like e.g. Cl, Br, I, mesylate, triflate, tosylate; and Sp, Y⁰ andL are as defined hereinbefore, in the presence of a strong base,yielding the indole derivative of the formula 2(v)

[0165] 2.) 1.) halogen-metal exchange of the derivative of the formula2(v) using an alkyllithium reagent or lithium metal; and

[0166] 2.) trans-metallation of the reaction product according to theprevious step using:

[0167] i) a trialkyl tin halide;

[0168] ii) alkyl borate; or

[0169] iii) zinc chloride; and

[0170] 3.) cross-coupling of the reaction product according to theprevious step using R²—X, wherein R² is defined as hereinbefore and X isF, Cl, Br, I or triflate, under transition metal catalysis yielding theproduct of the formula I.1; or

[0171] d) 1.) N-alkylation of the indole derivative of the formula 2(iv)using the electrophilic reagent X-Sp-C(═Y⁰)-L, wherein X is a leavinggroup, like e.g. Cl, Br, I, mesylate, triflate, tosylate; and Sp, Y⁰ andL are as defined hereinbefore, in the presence of a strong base,yielding the indole derivative of the formula 2(v) as definedhereinbefore; and

[0172] 2.) cross-coupling of the indole derivative of the formula 2(v)with an organometallic species such as, but not limited to

[0173] i) a stannane derivative of the formula R²—SnR′₃, wherein R² isdefined as hereinbefore and R′ is a C₁₋₈alkyl or aryl group; or

[0174] ii) a boronic acid derivative R²—B(OH)₂ and R²—B(OR′)₂, whereinR² and R′ are defined as hereinbefore;

[0175] under transition metal catalysis yielding the product of theformula I.1.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0176] The following definitions apply unless otherwise noted:

[0177] As used herein, the term (C_(1-n)) alkyl or C_(1-n)-alkyl,wherein n is an integer, either alone or in combination with anotherradical, are intended to mean acyclic straight or branched chain alkylradicals containing 1 to n carbon atoms respectively. Examples of suchradicals include methyl, ethyl, n-propyl, 1-methylethyl (i-propyl),n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl(tert.-butyl), n-pentyl, etc.. In the following the term Me denotes amethyl group.

[0178] If an alkyl group is substituted by halogen, it is preferablymono-, di- or trisubstituted with fluorine or monosubstituted bychlorine or bromine. Preferred alkyl-groups which are trisubstitutedwith fluorine have a terminal CF₃ group.

[0179] As used herein, the term (C_(2-n)) alkenyl, wherein n is aninteger, either alone or in combination with another radical, isintended to mean an unsaturated, acyclic straight chain radicalcontaining two to n carbon atoms, at least two of which are bonded toeach other by a double bond. Examples of such radicals are ethenyl(vinyl), 1-propenyl, 2-propenyl, 1-butenyl, etc..

[0180] As used herein, the term (C_(2-n)) alkynyl, wherein n is aninteger, either alone or in combination with another group, is intendedto mean an unsaturated, acyclic straight chain radical containing 2 to ncarbon atoms, at least two of which are bonded to each other by a triplebond. Examples of such radicals are ethynyl, 1-propynyl, 2-propynyl,etc.

[0181] As used herein, the term (C_(3-n))cycloalkyl, wherein n is aninteger, either alone or in combination with another radical, means acycloalkyl radical containing from three to n carbon atoms and includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0182] As used herein, the term (C_(5-n))cycloalkenyl, wherein n is aninteger, either alone or in combination with another radical, means anunsaturated cyclic radical containing five to n carbon atoms. Examplesare cyclopentenyl and cyclohexenyl.

[0183] As used herein the term (C_(1-n))alkyl-(C_(3-m))cycloalkyl,wherein n and m are integers, either alone or in combination withanother radical, means a branched or straight chain alkyl radical having1 to n C-atoms to which a cycloalkyl radical containing from three to mC-atoms is covalently bonded. Preferably the alkyl radical is a straightchain and the cycloalkyl radical is linked to its terminal C-atom.Examples of (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl include cyclopropytmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl,2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl,3-cyclopentylpropyl, 3-cyclohexylpropyl, etc..

[0184] As used herein, the terms alkyl-aryl, alkyl-HCy, alkyl-Hetaryl,alkyl-Het, etc. mean an alkyl radical to which an aryl, HCy, Hetaryl,Het group is bonded, respectively. Examples of (C₁₋₃)alkyl-aryl arebenzyl (phenylmethyl), phenylethyl and phenylpropyl.

[0185] As used herein, the term “carboxy protecting group” (CPG) definesprotecting groups that can be used during synthetic transformation andare listed in Greene, “Protective Groups in Organic Chemistry”, JohnWiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis,Biology”, Vol. 3, Academic Press, New York (1981), the disclosures ofwhich are hereby incorporated by reference.

[0186] A-carboxyl group is usually protected as an ester that can becleaved to give the carboxylic acid. Protecting groups that can be usedinclude: 1) alkyl esters such as methyl, trimethylsilylethyl andt-butyl, 2) aralkyl esters such as benzyl and substituted benzyl, or 3)esters that can be cleaved by mild base treatment or mild reductivemeans such as trichloroethyl and phenacyl esters.

[0187] As used herein, the term “aryl” either alone or in combinationwith another radical means a 6- or 10-membered aryl, i.e. an aromaticradical containing six or ten carbon atoms, for example phenyl,1-naphthyl or 2-naphthyl. The most preferred meaning of aryl is phenyl.

[0188] As used herein the term heteroatom means O, S or N.

[0189] As used herein, the term “heterocycle”, either alone or incombination with another radical, means a monovalent radical derived byremoval of a hydrogen from a four-, five-, six-, or seven-memberedsaturated or unsaturated (including aromatic) heterocycle containingfrom one to four heteroatoms selected from nitrogen, oxygen and sulfur.Examples of such heterocycles include, but are not limited to,azetidine, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole,thiophene, hydantoin, diazepine, 1H-imidazole, isoxazole, thiazole,tetrazole, piperidine, piperazine, homopiperidine, homopiperazine,1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxideor pyrimidine, or the following heterocycles:

[0190] As used herein, the term “9- or 10-membered heterobicycle” or“heterobicycle” either alone or in combination with another radical,means a heterocycle as defined above fused to one or more other cycle,be it a heterocycle or any other cycle. Examples of such heterobicyclesinclude, but are not limited to, indole, benzimidazole,thiazolo[4,5-b]-pyridine, quinoline, or coumarin, or the following:

[0191] As used herein, the term “Het” defines a 4-, 5-, 6- or 7-memberedheterocycle having 1 to 4 heteroatoms selected from O, N and S, whichmay be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or11-membered heterobicycle having 1 to 5 heteroatoms wherever possible,selected from O, N and S, which may be saturated, unsaturated oraromatic, unless specified otherwise.

[0192] As used herein, the term “HCy” defines a saturated or unsaturated4-, 5-, 6- or 7-membered monocyclic heterocycle having 1 to 3heteroatoms selected from O, N and S, unless specified otherwise.

[0193] As used herein, the term “Hetaryl” defines an aromatic 5- or6-membered monocyclic heterocycle having 1 or 2 heteroatoms selectedfrom O, N and S, or a 9- or 10-membered aromatic heterobicycle having 1to 4 heteroatoms selected from O, N, and S, unless specified otherwise.

[0194] As used herein, the term “halo” means a halogen atom and includesfluorine, chlorine, bromine and iodine.

[0195] As used herein, the term “OH” refers to a hydroxyl group. It iswell known to one skilled in the art that hydroxyl groups may besubstituted by functional group equivalents. Examples of such functionalgroup equivalents that are contemplated by this invention include, butare not limited to, ethers, sulfhydryls, and primary, secondary ortertiary amines.

[0196] As used herein, the term “SH” refers to a sulfhydryl group. It isintended within the scope of the present invention that, whenever a “SH”or “SR” group is present, it can also be substituted by any otherappropriate oxidation state such as SOR, SO₂R, or SO₃R.

[0197] It is intended that the term “substituted” when applied inconjunction with a radical having more than one moiety such asC₁₋₆alkyl-aryl, or C₁₋₆alkyl-Het, such substitution applies to bothmoieties i.e. both the alkyl and aryl or Het moieties can be substitutedwith the defined substituents.

[0198] As used herein, the term “COOH” refers to a carboxylic acidgroup. It is well known to one skilled in the art that carboxylic acidgroups may be substituted by functional group equivalents. Examples ofsuch functional group equivalents that are contemplated by thisinvention include, but are not limited to, esters, amides, imides,boronic acids, tetrazoles, triazoles, N-acylsulfonyidiamides(RCONHSO₂NR₂), and N-acylsulfonamides (RCONHSO₂R).

[0199] As used herein, the term “functional group equivalent” isintended to mean an element or a substituted derivative thereof, that isreplaceable by another element that has similar electronic,hybridization or bonding properties.

[0200] As used herein, the term “metal catalyst” is intended to mean ametal such as palladium (0) or palladium (2) for use in a cross-couplingreaction. Examples of such palladium catalysts include, but are notlimited to, Pd(Ph₃)₄, Pd/C, Pd(OAc)₂, PdCl₂, and the like. Alternativemetals that can catalyze cross-coupling reactions include, but are notlimited to, complexes of Ni, Rh, Ru and Ir, like for example: Ni(acac)₂,Ni(OAc)₂, or NiCl₂.

[0201] The term “detectable label” refers to any group that may belinked to the polymerase or to a compound of the present invention suchthat when the compound is associated with the polymerase target, suchlabel allows recognition either directly or indirectly of the compoundsuch that it can be detected, measured and quantified. Examples of such“labels” are intended to include, but are not limited to, fluorescentlabels, chemiluminescent labels, colorimetric labels, enzymatic markers,radioactive isotopes and affinity tags such as biotin. Such labels areattached to the compound or to the polymerase by well known methods.

[0202] The term “affinity tag” means a ligand (that is linked to thepolymerase or to a compound of the present invention) whose strongaffinity for a receptor can be used to extract from a solution theentity to which the ligand is attached. Examples of such ligands includebiotin or a derivative thereof, a histidine polypeptide, a polyarginine,an amylose sugar moiety or a defined epitope recognizable by a specificantibody. Such affinity tags are attached to the compound or to thepolymerase by well-known methods.

[0203] The term “photoreactive group” means a group that is transformed,upon activation by light, from an inert group to a reactive species,such as a free radical. Examples of such groups include, but are notlimited to, benzophenones, azides, and the like.

[0204] The term “salt thereof” means any acid and/or base addition saltof a compound according to the invention; preferably a pharmaceuticallyacceptable salt thereof.

[0205] The term “pharmaceutically acceptable salt” means a salt of acompound of formula (1) which is, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response, andthe like, commensurate with a reasonable benefit/risk ratio, generallywater or oil-soluble or dispersible, and effective for their intendeduse. The term includes pharmaceutically-acceptable acid addition saltsand pharmaceutically-acceptable base addition salts. Lists of suitablesalts are found in, e.g., S. M. Birge et al., J. Pharm. Sci., 1977, 66,pp. 1-19, which is hereby incorporated by reference in its entirety.

[0206] The term “pharmaceutically-acceptable acid addition salt” meansthose salts which retain the biological effectiveness and properties ofthe free bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and thelike, and organic acids such as acetic acid, trifluoroacetic acid,adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoicacid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid,citric acid, digluconic acid, ethanesulfonic acid, glutamic acid,glycolic acid, glycerophosphoric acid, hemisulfic acid, hexanoic acid,formic acid, fumaric acid, 2-hydroxyethane-sulfonic acid (isethionicacid), lactic acid, hydroxymaleic acid, malic acid, malonic acid,mandelic acid, mesitylenesulfonic acid, methanesulfonic acid,naphthalene-sulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid,oxalic acid, pamoic acid, pectinic acid, phenylacetic acid,3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaricacid, p-toluenesulfonic acid, undecanoic acid, and the like.

[0207] The term “pharmaceutically-acceptable base addition salt” meansthose salts which retain the biological effectiveness and properties ofthe free acids and which are not biologically or otherwise undesirable,formed with inorganic bases such as ammonia or hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum,and the like. Particularly preferred are the ammonium, potassium,sodium, calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include salts ofprimary, secondary, and tertiary amines, quaternary amine compounds,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion-exchange resins, such as methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,isopropylamine, tripropylamine, tributylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine,choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, N-ethylpiperidine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, N,N′-dibenzylethylenediamine, polyamine resins, and thelike. Particularly preferred organic nontoxic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline,and caffeine.

[0208] The term “antiviral agent” as used herein means an agent(compound or biological) that is effective to inhibit the formationand/or replication of a virus in a mammal. This includes agents thatinterfere with either host or viral mechanisms necessary for theformation and/or replication of a virus in a mammal. Antiviral agentsinclude, for example, ribavirin, amantadine, VX-497 (merimepodib, VertexPharmaceuticals), VX-498 (Vertex Pharmaceuticals), Levovirin,Viramidine, Ceplene (maxamine), XTL-001 and XTL-002 (XTLBiopharmaceuticals).

[0209] The term “other anti-HCV agent” as used herein means those agentsthat are effective for diminishing or preventing the progression ofhepatitis C related symptoms of disease. Such agents can be selectedfrom: immunomodulatory agents, inhibitors of HCV NS3 protease, otherinhibitors of HCV polymerase or inhibitors of another target in the HCVlife cycle.

[0210] The term “immunomodulatory agent” as used herein means thoseagents (compounds or biologicals) that are effective to enhance orpotentiate the immune system response in a mammal. Immunomodulatoryagents include, for example, class I interferons (such as α-, β-, δ- andomega interferons, tau-interferons, consensus interferons andasialo-interferons), class II interferons (such as γ-interferons) andpegylated interferons.

[0211] The term “inhibitor of HCV NS3 protease” as used herein means anagent (compound or biological) that is effective to inhibit the functionof HCV NS3 protease in a mammal. Inhibitors of HCV NS3 protease include,for example, those compounds described in WO 99/07733, WO 99/07734, WO00/09558, WO 00/09543, WO 00/59929 or WO 02/060926, the BoehringerIngelheim clinical candidate identified as BILN 2061 and the Vertexpre-development candidate identified as VX-950. Particularly, compounds#2, 3, 5, 6, 8, 10, 11, 18, 19, 29, 30, 31, 32, 33, 37, 38, 55, 59, 71,91, 103, 104, 105, 112, 113, 114, 115, 116, 120, 122, 123, 124, 125, 126and 127 disclosed in the table of pages 224-226 in WO 02/060926, can beused in combination with the compounds of the present invention

[0212] The term “other inhibitor of HCV polymerase” as used herein meansan agent (compound or biological) that is effective to inhibit thefunction of HCV polymerase in a mammal, whereby this agent has astructure different from the compounds according to this invention andpreferably binds to a site of the HCV polymerase different from the sitetargeted by the compounds according to this invention. Other inhibitorsof HCV polymerase include non-nucleosides, for example, those compoundsdescribed in: WO 03/040112 (Rigel), WO 02/100846 A1 (Shire), WO02/100851 A2 (Shire), WO 01/85172 A1 (GSK), WO 02/098424 A1 (GSK), WO00/06529 (Merck), WO 02/06246 A1 (Merck), EP 1 256 628 A2 (Agouron).Furthermore other inhibitors of HCV polymerase also include nucleosideanalogs, for example, those compounds described in: WO 01/90121 A2(Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), WO 02/057287A2 (Merck/Isis) and WO 02/057425 A2 (Merck/Isis).

[0213] The term “inhibitor of another target in the HCV life cycle” asused herein means an agent (compound or biological) that is effective toinhibit the formation and/or replication of HCV in a mammal other thanby inhibiting the RNA dependent RNA polymerase of HCV. This includesagents that interfere with either host or HCV viral mechanisms necessaryfor the formation and/or replication of HCV in a mammal. Inhibitors ofanother target in the HCV life cycle include, for example, agents thatinhibit a target selected from a HCV helicase, HCV NS2/3 protease andHCV IRES. Specific examples of inhibitors of another target in the HCVlife cycle include ISIS-14803 (ISIS Pharmaceuticals).

[0214] The term “HIV inhibitor” as used herein means an agent (compoundor biological) that is effective to inhibit the formation and/orreplication of HIV in a mammal. This includes agents that interfere witheither host or viral mechanisms necessary for the formation and/orreplication of HIV in a mammal. HIV inhibitors include, for example,nucleosidic inhibitors, non-nucleosidic inhibitors, protease inhibitors,fusion inhibitors and integrase inhibitors.

[0215] The term “HAV inhibitor” as used herein means an agent (compoundor biological) that is effective to inhibit the formation and/orreplication of HAV in a mammal. This includes agents that interfere witheither host or viral mechanisms necessary for the formation and/orreplication of HAV in a mammal. HAV inhibitors include Hepatitis Avaccines, for example, Havrix® (GlaxoSmithKline), VAQTA® (Merck) andAvaxim® (Aventis Pasteur).

[0216] The term “HBV inhibitor” as used herein means an agent (compoundor biological) that is effective to inhibit the formation and/orreplication of HBV in a mammal. This includes agents that interfere witheither host or viral mechanisms necessary for the formation and/orreplication of HBV in a mammal. HBV inhibitors include, for example,agents that inhibit HBV viral DNA polymerase or HBV vaccines. Specificexamples of HBV inhibitors include Lamivudine (Epivir-HBV®), AdefovirDipivoxil, Entecavir, FTC (Coviracil®), DAPD (DXG), L-FMAU (Clevudine®),AM365 (Amrad), Ldt (Telbivudine), monoval-LdC (Valtorcitabine),ACH-126,443 (L-Fd4C) (Achillion), MCC478 (Eli Lilly), Racivir (RCV),Fluoro-L and D nucleosides, Robustaflavone, ICN 2001-3 (ICN), Bam 205(Novelos), XTL-001 (XTL), Imino-Sugars (Nonyl-DNJ) (Synergy), HepBzyme;and immunomodulator products such as: interferon alpha 2b, HE2000(Hollis-Eden), Theradigm (Epimmune), EHT899 (Enzo Biochem), Thymosinalpha-1 (Zadaxin®), HBV DNA vaccine (PowderJect), HBV DNA vaccine(Jefferon Center), HBV antigen (OraGen), BayHep B® (Bayer), Nabi-HB®(Nabi) and Anti-hepatitis B (Cangene); and HBV vaccine products such asthe following: Engerix B, Recombivax HB, GenHevac B, Hepacare, Bio-HepB, TwinRix, Comvax, Hexavac.

[0217] The term “class I interferon” as used herein means an interferonselected from a group of interferons that all bind to receptor type I.This includes both naturally and synthetically produced class Iinterferons. Examples of class I interferons include α-, β-, omegainterferons, tau-interferons, consensus interferons, asialo-interferons.

[0218] The term “class II interferon” as used herein means an interferonselected from a group of interferons that all bind to receptor type II.Examples of class II interferons include γ-interferons.

[0219] Specific preferred examples of some of these agents are listedbelow:

[0220] antiviral agents: ribavirin and amantadine;

[0221] immunomodulatory agents: class I interferons, class IIinterferons and pegylated interferons;

[0222] HCV NS3 protease inhibitors;

[0223] other inhibitors of the HCV polymerase: nucleosidic andnon-nucleosidic inhibitors;

[0224] inhibitor of another target in the HCV life cycle that inhibits atarget selected from: HCV NS2/3 protease or internal ribosome entry site(IRES);

[0225] HIV inhibitors: nucleosidic inhibitors, non-nucleosidicinhibitors, protease inhibitors, fusion inhibitors and integraseinhibitors; or

[0226] HBV inhibitors: agents that inhibit viral DNA polymerase or is anHBV vaccine.

[0227] As discussed above, combination therapy is contemplated wherein acompound of formula (I), or a pharmaceutically acceptable salt thereof,is co-administered with at least one additional agent selected from: anantiviral agent, an immunomodulatory agent, an inhibitor of HCV NS3protease, another inhibitor of HCV polymerase, an inhibitor of anothertarget in the HCV life cycle, an HIV inhibitor, an HAV inhibitor and anHBV inhibitor. Examples of such agents are provided in the Definitionssection above. These additional agents may be combined with thecompounds of this invention to create a single pharmaceutical dosageform. Alternatively these additional agents may be separatelyadministered to the patient as part of a multiple dosage form, forexample, using a kit. Such additional agents may be administered to thepatient prior to, concurrently with, or following the administration ofwherein a compound of formula (I), or a pharmaceutically acceptable saltthereof.

[0228] As used herein, the term “treatment” means the administration ofa compound or composition according to the present invention toalleviate or eliminate symptoms of the hepatitis C disease and/or toreduce viral load in a patient.

[0229] As used herein, the term “prevention” means the administration ofa compound or composition according to the present inventionpost-exposure of the individual to the virus but before the appearanceof symptoms of the disease, and/or prior to the detection of the virusin the blood.

[0230] The following signs - - - and

are used interchangeably in subformulas to indicate the bond, or in thecase of a spirocyclic group the atom, which is bonded to the rest of themolecule as defined.

[0231] As used herein, the designation whereby a bond to a substituent Ris drawn as emanating from the center of a ring, such as, for example,

[0232] means that the substituent R may be attached to any free positionon the ring that would otherwise be substituted by a hydrogen atom,unless specified otherwise.

PREFERRED EMBODIMENTS

[0233] As long as not stated otherwise, all groups, substituents andindices, like e.g. R¹, R^(1q), R ², R^(2h), R^(2q), R³, R⁴, R^(4b), R⁵,R^(5a), R^(5b), R^(6a), R^(6b), R^(7a), R^(8a), R^(7b), R^(8b), R^(9a),R^(9b), R¹¹, R¹², R¹³, R¹⁴, R²¹, R³¹, R³², R³³, R³⁵, R⁵¹, R⁵², R⁶⁰,R¹¹¹, R¹¹², R¹¹⁷, R¹⁵⁰, R¹⁶⁰, R¹⁶¹, R¹⁶² R¹⁶³, R¹⁷⁰, R^(O), R^(C),R^(L), R^(N1), R^(N2), R^(N3), R^(N4), R^(Q), A, B, L, M¹, M², M³, M⁴,Q¹, Q^(1a), Q^(1b), Q^(1c), Q², Q^(2a), Q^(2b), Q^(2c), W¹, W², Y⁰, Y¹,Y², Y³, X, Z, Sp, Het, HCy, Hetaryl, k₁, q, qa, and qb, have themeanings as defined hereinbefore and hereinafter. In the following thepreferred embodiments, groups, substituents and indices according tothis invention are described.

[0234] In a preferred embodiment of the first aspect of the invention,there is provided an isomer, enantiomer, diastereoisomer or tautomer ofa compound, represented by formula I:

[0235] wherein:

[0236] either A or B is N and the other B or A is C, wherein - - -between two C-atoms represents a double bond and - - - between a C-atomand a N-atom represents a single bond,

[0237] the group —C(═Y¹)-Z is covalently linked to either M² or M³,

[0238] M¹ is CR^(4a),

[0239] M² or M³ is CR⁵,

[0240] M⁴ is CR^(4b),

[0241] and in addition one or two of the groups selected from M¹, M², M³and M⁴ may also be N, with the proviso that the group M² or M³ to which—C(═Y¹)-Z is linked is an C-atom,

[0242] Sp is a spacer group selected from —(CR⁵¹R⁵²)k₁—, wherein

[0243] k1 is 1, 2 or 3;

[0244] R⁵¹, R⁵² are independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, or

[0245] R⁵¹ and R⁵² are covalently bonded together and to the carbon-atomto which they are attached to form a (C₃₋₆)cycloalkyl group,

[0246] said alkyl, cycloalkyls or alkyl-cycloalkyl being optionallysubstituted by halogen, hydroxy, (C₁₋₆)alkoxy, cyano, amino,—NH(C₁₋₄-alkyl) and/or —N(C₁₋₄-alkyl)₂;

[0247] Y⁰ is O, S, NR¹¹ or CR¹²R¹³, wherein

[0248] R¹¹, R¹², R¹³ are each independently defined as R^(O);

[0249] R¹³ may also be COOR^(O) or SO₂R^(C);

[0250] wherein R^(C) and each R^(O) is optionally substituted with R¹⁵⁰;

[0251] or both R¹² and R¹³ are covalently bonded together and to thecarbon-atom to which they are attached to form a 3, 4, 5, 6 or7-membered saturated or 5, 6 or 7-membered unsaturated cyclic systemwhereby the 5, 6 or 7-membered saturated or unsaturated cyclic systemmay contain 1 to 3 heteroatoms selected from N, O or S; said cyclicsystems being optionally substituted with R¹⁵⁰;

[0252] L is C₁₋₆alkyl, (C₃₋₆)cycloalkyl, C₁₋₆alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, aryl, (C₁₋₆alkyl)aryl, Het, (C₁₋₆)alkyl-Het, all of whichbeing optionally substituted with R⁶⁰;

[0253] or if Y⁰ is CR¹²R¹³, then L may also be H;

[0254] or if Y⁰ is O, then L may also be OR^(C),

[0255] wherein R^(C) is optionally substituted with R⁶⁰;

[0256] or if Y⁰ is O, S or NR¹¹, then L may also be N(R^(N2))R^(N1),NR^(N3)—N(R^(N2))R^(N1), NR^(N3)—NR^(N2)—CO—R^(C),NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1), NR^(N2)—SO₂—R^(C), NR^(N2)—CO—R^(C),NR^(N3)—CO—N(R^(N2))R^(N1) or N(R^(N1))OR^(O);

[0257] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1), R^(N2) and/or R^(N3), and R^(C) and R^(O) being optionallysubstituted with R⁶⁰;

[0258] or if Y⁰ is O or S, then L may also be OR^(6a) orN(R^(5a))R^(6a), wherein R^(5a) is defined as R^(N2),

[0259] and wherein R^(6a) is:

[0260] wherein R^(7a) and R^(8a) are each independently defined asR^(O), wherein said R^(O) is optionally substituted with R⁶⁰; or

[0261] R^(7a) and R^(8a) are covalently bonded together to form a(C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3heteroatom selected from O, N, and S; and when L is N(R^(5a))R^(6a),either of R^(7a) or R^(8a) may be covalently bonded to R^(5a) to form anitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkylor heterocycle being optionally substituted by R¹⁵⁰; and

[0262] Y² is O or S;

[0263] R^(9a) is defined as R^(O), wherein said R^(O) is optionallysubstituted with R⁶⁰; or

[0264] R^(9a) is covalently bonded to either of R^(7a) or R^(8a) to forma 5- or 6-membered heterocycle;

[0265] Q¹ is aryl, Het, (C₁₋₆) alkyl-aryl, (C₁₋₆)alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which being optionallysubstituted with R⁶⁰;

[0266] Y¹ is O, S or NR¹⁴, wherein R¹⁴ is H or (C₁₋₆) alkyl;

[0267] Z is defined as

[0268] a) OR^(O);

[0269] b) SO₂R^(C);

[0270] c) N(R^(N2))R^(N1);

[0271] d) NR^(N3)—N(R^(N2))R^(N1);

[0272] e) NR^(N3)—NR^(N2)—CO—R^(C);

[0273] f) NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1);

[0274] g) NR^(N2)—SO₂—R^(C) or

[0275] h) NR^(N2)—CO—R^(C);

[0276] i) COOR^(O);

[0277] j) N(R^(N1))OR^(O);

[0278] wherein R^(O) and R^(C) are optionally substituted with R⁶⁰; and

[0279] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1), R^(N2), and/or R^(N3), being optionally substituted with R⁶⁰;

[0280] or Z is OR^(6b) or N(R^(5b))R^(6b) wherein R^(5b) is defined asR^(N2) and R^(6b) is:

[0281] wherein R^(7b), R^(8b), Y³, R^(9b), Q², are defined as R^(7a),R^(8a), Y², R^(9a), Q¹, respectively;

[0282] R² is selected from: halogen or R²¹, wherein R²¹ is aryl or Het,said R²¹ is optionally substituted with R¹⁵⁰;

[0283] R³ is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl,(C₁₋₃)alkyl-(C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl,(C₁₋₃)alkyl-(C₆₋₁₀)bicycloalkyl, (C₆₋₁₀)bicycloalkenyl,(C₁₋₃)alkyl-(C₆₋₁₀)bicycloalkenyl, HCy or (C₁₋₃)alkyl-HCy,

[0284] wherein HCy is a saturated or unsaturated 4 to 7-memberedheterocyclic group with 1 to 3 heteroatoms selected from O, S and N;

[0285] said alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl,bicycloalkenyl, HCy and alkyl-HCy being optionally substituted with from1 to 4 substituents selected from: a) halogen;

[0286] b) (C₁₋₆)alkyl optionally substituted with:

[0287] OR³¹ or SR³¹ wherein R³¹ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or

[0288] N(R³²)₂ wherein each R³² is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³² arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle;

[0289] c) OR³³ or SR³³ wherein R³³ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkylor (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl;

[0290] d) N(R³⁵)₂ wherein each R³⁵ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³⁵ arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle;

[0291] R^(4a), R^(4b), R⁵ each are independently H or defined as R¹⁵⁰;

[0292] R⁶⁰ is each defined as 1 to 4 substituents independently selectedfrom:

[0293] 1 to 3 substituents selected from halogen;

[0294] one of each substituent selected from: OPO₃H, NO₂, cyano, azido,C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl, SO₃H; and

[0295] 1to 3 substituents selected from:

[0296] a) (C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyloptionally containing 1 or 2 heteroatoms selected from N, O and S;(C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, all of whichoptionally being substituted with R¹⁵⁰;

[0297] b) OR^(O);

[0298] c) OC(O)R^(O);

[0299] d) SR^(O), SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C) orCONR^(N2)S₂R^(C);

[0300] e) N(R^(N2))R^(N1), N(R^(N2))COOR^(C), or N(R^(N2))SO₂R^(C);

[0301] f) N(R^(N2))COR^(C);

[0302] g) N(R^(N3))CON(R^(N2))R^(N1);

[0303] h) N(R^(N3))COCOR^(C), N(R^(N3))COCOOR^(O) orN(R^(N3))COCON(R^(N2))R^(N1);

[0304] i) COR^(O);

[0305] j) COOR^(O);

[0306] k) CON(R^(N2))R^(N1);

[0307] l) aryl, Het, (C₁₋₄alkyl)aryl or (C₁₋₄alkyl)Het, all of whichoptionally being substituted with R¹⁵⁰;

[0308] wherein said R^(N1), R^(C) and R^(O) are each independentlyoptionally substituted with R¹⁵⁰ as defined,

[0309] R¹⁵⁰ is each defined as 1 to 4 substituents independentlyselected from:

[0310] 1 to 3 substituents selected from halogen;

[0311] one of each substituent selected from: OPO₃H, NO₂, cyano, azido,C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl; and

[0312] 1 to 3 substituents selected from:

[0313] a) (C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyloptionally containing 1 or 2 heteroatoms selected from N, O and S;(C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, all of whichoptionally substituted with R¹⁶⁰;

[0314] b) OR^(O);

[0315] c) OC(O)R^(O);

[0316] d) SR^(O), SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C) orCON(R^(N2))SO₂R^(C);

[0317] e) N(R^(N2))R^(N1), N(R^(N2))COOR^(C), or N(R^(N2))SO₂R^(C);

[0318] f) N(R^(N2))COR^(C);

[0319] g) N(R^(N3))CON(R^(N2))R^(N1);

[0320] h) N(R^(N3))COCOR^(C), N(R^(N3))COCOOR^(O) orN(R^(N3))COCON(R^(N2))R^(N1);

[0321] wherein R^(N1) is as defined or OH, O-C₁₋₄-alkyl;

[0322] i) COR^(O);

[0323] j) COOR^(O);

[0324] k) tetrazole or CON(R^(N2))R^(N1);

[0325] wherein said R^(N1), R^(C) and/or R^(O) are optionallysubstituted with R¹⁶⁰ as defined;

[0326] R¹⁶⁰ is each defined as 1, 2 or 3 substituents independentlyselected from:

[0327] 1, 2 or 3 fluorine substituents; and

[0328] one of each substituent selected from tetrazole, chlorine,bromine, iodine, CN, nitro, C₁₋₄alkyl, CF₃, COOR¹⁶¹, SO₃H, SR¹⁶¹,SO₂R¹⁶³, OR¹⁶¹, N(R¹⁶²)₂, SO₂N(R¹⁶²)₂, SO₂NR¹⁶²COR¹⁶², NR¹⁶²SO₂R⁶³, NRC⁶²COR¹⁶², or CON(R¹⁶²)₂, wherein R¹⁶¹, R¹⁶³ and each R¹⁶² isindependently (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; and R¹⁶¹ and each R¹⁶² may eachindependently also be H; or both R¹⁶² are covalently bonded together andto the nitrogen to which they are attached to form a 5, 6 or 7-memberedsaturated heterocycle;

[0329] R^(O), R^(C) are independently defined as (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₆)alkyl-aryl and (C₁₋₆)alkyl-Het; and

[0330] R^(O) may also be H;

[0331] R^(N1) is independently selected from H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₆)alkyl-aryl, (C₁₄)alkyl-Het; or

[0332] R^(N2), R^(N3), R^(N4) are independently H, CH₃, (C₂₋₆alkyl),(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; wherein said alkyl,cycloalkyl or alkylcycloalkyl is optionally substituted with hydroxy,halogen, carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkyl, C₁₋₆alkoxy, amino,—NH(C₁₋₆-alkyl) and/or —N(C₁₋₄-alkyl)₂; and wherein said CH₃ isoptionally substituted with halogen, carboxy or C₁₋₆alkoxycarbonyl; and

[0333] in the case

[0334] a) of a group N(R^(N2))R^(N1) the substituents R^(N2) and R^(N1);or

[0335] b) of a group NR^(N3)—N(R^(N2))R^(N1) the substituents R^(N3) andR^(N1), or R^(N2) and R^(N1);

[0336] may be covalently bonded together to form a 4-, 5-, 6- or7-membered saturated or unsaturated N-containing heterocycle or a 8-,9-, 10- or 11-membered N-containing heterobicycle each may haveadditionally from 1 to 3 heteroatoms selected from O, N, and S;

[0337] wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, or a 8-, 9-, 10- or11 -membered heterobicycle having 1 to 5 heteroatoms selected from O, Nand S;

[0338] or a salt thereof.

[0339] Core:

[0340] This invention comprises compounds of the formulas Ia and Ib

[0341] wherein the compounds of the formula Ia are preferred.

[0342] Furthermore this invention comprises compounds according to theformulas Ic and Id

[0343] wherein the compounds of the formula Ic are preferred.

[0344] More explicitly, this invention comprises compounds of thefollowing formulas

[0345] wherein R¹ denotes the group -Sp-C(═Y⁰)-L.

[0346] Also explicitly, this invention further comprises compounds ofthe following formulas:

[0347] wherein R¹ denotes the group -Sp-C(═Y⁰)-L.

[0348] Preferably the groups M¹ and M⁴ are CR^(4a) and CR^(4b),respectively.

[0349] The group M² or M³ to which the group —C(═Y¹)-Z is covalentlylinked is C and the other group M³ or M² is preferably CR⁵.

[0350] Therefore those compounds are preferred which are described bythe following group of formulas I.1 to I.4

[0351] A group of most preferred compounds is described by the formulaI.1

[0352] Another group of preferred compounds is described by the formulaI.4 as given above.

[0353] Sp:

[0354] The preferred meaning of the spacer group Sp is a group selectedfrom —(CR⁵¹R⁵²)_(k1)—, wherein k1 is 1, 2 or 3; and R⁵¹, R⁵² areindependently H or (C₁₋₃)alkyl, in particular H or methyl; and/or R⁵¹,R⁵² are covalently bonded together and to the carbon-atom to which theyare attached to form a cyclopropyl, cyclobutyl or cyclopentyl group.

[0355] More preferably Sp is a spacer group selected from —CH₂—,—CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂— and

[0356] Most preferably Sp is —CH₂—.

[0357] Y⁰:

[0358] According to a first preferred embodiment of this invention Y⁰ isO or S, most preferably O.

[0359] According to a second preferred embodiment of this invention Y⁰and L are covalently bonded to form a 5, 6, 7 or 8-membered mono- or a8, 9, 10 or 11-membered bicyclic group which may contain 1, 2 or 3heteroatoms selected from N, O and S, wherein the mono- or bicyclicgroup is optionally substituted with R⁶⁰.

[0360] In this second embodiment those compounds are preferred, whereinY⁰ and L are covalently bonded to form an unsaturated 5 or 6-memberedmonocyclic group which may contain 1 or 2 heteroatoms selected from N, Oand S, wherein the monocyclic group is optionally substituted with R⁶⁰.Most preferably said monocyclic group is a monocyclic aromatic orheteroaromatic group. Preferred examples of such (hetero)aromatic groupsare phenyl, pyridine and thiazole, being optionally substituted asdescribed.

[0361] Therefore preferred groups of the subformula

[0362] Beside said preferred first and second embodiment, Y⁰ may also beNR¹¹ or CR¹²R¹³ wherein R¹¹, R¹², R¹³ are defined as hereinbefore.Preferred meanings of R¹¹, R¹², R¹³ are independently H or C₁₋₆alkyl;most preferably H or methyl.

[0363] L:

[0364] According to a first embodiment the group L has one of thefollowing meanings:

[0365] a) C₁₋₆alkyl, (C₃₋₆)cycloalkyl, C₁₋₆alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, all of which being optionally substituted with R⁶⁰; or

[0366] b) if Y⁰ is CR¹²R¹³, then L may also be H; or

[0367] c) if Y⁰ is O, then L may also be OR^(C),

[0368] wherein R^(C) is optionally substituted with R⁶⁰,

[0369] wherein R¹², R¹³, R⁶⁰ and R^(C) are as defined hereinbefore.

[0370] According to a preferred second embodiment, wherein Y⁰ is O, S orNR¹¹, the group L has one of the following meanings:

[0371] a) L is N(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(C), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—SO₂—R^(C) or N(R^(N2))OR^(O),

[0372] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1), R^(N2) and/or R^(N3), and R^(C) being optionally substitutedwith R⁶⁰; or

[0373] b) L is N(R^(5a))R^(6a) wherein R^(5a) is defined as R^(N2) andR^(6a) is:

[0374] or R^(6a) is:

[0375] wherein R^(7a) and R^(8a) are each independently defined asR^(O), wherein said R^(O) is optionally substituted with R⁶⁰; or

[0376] R^(7a) and R^(8a) are covalently bonded together to form a second(C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3heteroatom selected from O, N, and S; and either of R^(7a) or R^(8a) maybe covalently bonded to R^(5a) to form a nitrogen-containing 5-or6-membered heterocycle, wherein said cycloalkyl or heterocycle beingoptionally substituted by R¹⁵⁰; and

[0377] W¹ is selected from

[0378] a) a single bond;

[0379] b) —CH₂—;

[0380] c) —CH₂—CH₂—; and

[0381] d) —CH═CH—;

[0382] Y² is O or S;

[0383] R^(9a) is defined as R^(O), wherein said R^(O) is optionallysubstituted with R⁶⁰; or

[0384] R^(9a) is covalently bonded to either of R^(7a) or R^(8a) to forma 5- or 6-membered heterocycle;

[0385] Q¹ is aryl, Het, (C₁₋₆) alkyl-aryl, (C₁₋₆) alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which being optionallysubstituted with R⁶⁰.

[0386] Y¹:

[0387] The group Y¹ is defined as O, S or NR¹⁴, wherein R¹⁴ is H or(C₁₋₆) alkyl; most preferably Y¹ is O.

[0388] Z:

[0389] Preferably the group Z is selected from the group of definitions:

[0390] a) OR^(O);

[0391] c) N(R^(N2))R^(N1);

[0392] g) NR^(N2)—SO₂—R^(C);

[0393] h) NR^(N3)—SO₂—N(R^(N2))R^(N1); or

[0394] i) NR^(N2)—CO—R^(C);

[0395] wherein R^(O) and R^(C) are optionally substituted with R⁶⁰; and

[0396] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1) and R^(N2), being optionally substituted with R⁶⁰;

[0397] or Z is OR^(6b) or N(R^(5b))R^(6b) wherein R^(5b) is defined asR^(N2) and R^(6b) is:

[0398] or R^(6b) is:

[0399] wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a),R^(8a), Y², R^(9a), W¹ respectively; and

[0400] Q² is aryl, Het, (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-Het,(C₁₋₆)alkyl-CONH-aryl or (C₁₋₆)alkyl-CONH-Het, all of which beingoptionally substituted with R⁶⁰

[0401] or Q² is R¹⁶⁰

[0402] or Q² is selected from the group consisting of O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₆-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of whichbeing optionally substituted with R¹⁶⁰;.

[0403] In the case Z being defined as OR^(O), SO₂R^(C), COOR^(O) orOR^(6b), wherein R^(6b) is defined as above, then Y¹ is preferably O.

[0404] Sp, Y⁰, L, Y¹ and Z:

[0405] Those compounds according to this invention are preferred,wherein

[0406] Sp is a spacer group selected from —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH₂—CH₂— and

[0407] most preferably Sp is —CH₂—; and

[0408] Y⁰ is O or S; most preferably O;

[0409] L is N(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(C), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—SO₂—R^(C) or N(R^(N1) )OR^(O);

[0410] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1), R^(N2) and/or R^(N3), and R^(C) being optionally substitutedwith R⁶⁰; or

[0411] L is N(R^(5a))R^(6a) wherein R^(5a) is defined as R^(N2) andR^(6a) is:

[0412] or R^(6a) is:

[0413] Y¹ is O or S; most preferably O;

[0414] Z is defined as

[0415] a) OR^(O);

[0416] c) N(R^(N2))R^(N1); or

[0417] g) NR^(N2)—SO₂—R^(C);

[0418] wherein R^(O) and R^(C) are optionally substituted with R⁶⁰; and

[0419] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1) and R^(N2), being optionally substituted with R⁶⁰; or

[0420] Z is N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) andR^(6b) is:

[0421] or R^(6b) is:

[0422] wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a),R^(8a), Y², R^(9a), W¹ respectively; and

[0423] Q² is aryl, Het, (C₁₋₆) alkyl-aryl, (C₁₋₆) alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which being optionallysubstituted with R⁶⁰ or Q² is R¹⁶⁰

[0424] or Q² is selected from the group consisting of O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of whichbeing optionally substituted with R¹⁶⁰;

[0425] In the following, preferred groups of compounds according to thisinvention are described more specifically.

[0426] A first group of preferred compounds according to this inventionis defined by formula I.1a

[0427] wherein R^(N1), including any heterocycle formed by R^(N1) andR^(N2), is optionally substituted with R⁶⁰; and

[0428] Z is defined as

[0429] a) OR^(O);

[0430] c) N(R^(N2))R^(N1); or

[0431] g) NR^(N2)—SO₂—R^(C);

[0432] wherein R^(O) and R^(C) are optionally substituted with R⁶⁰; and

[0433] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1) and R^(N2), being optionally substituted with R⁶⁰; or

[0434] z is N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) andR^(6b) is:

[0435] or R^(6b) is:

[0436] wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a),R^(8a), Y², R^(9a), W¹ respectively; and

[0437] Q² is aryl, Het, (C₁₋₆) alkyl-aryl, (C₁₋₆) alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which being optionallysubstituted with R⁶⁰

[0438] or Q² is R¹⁶⁰

[0439] or Q² is selected from the group consisting of O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of whichbeing optionally substituted with R¹⁶⁰;.

[0440] A second group of preferred compounds according to this inventionis defined by formula I.1b

[0441] wherein

[0442] R^(5a) is defined as R^(N2);

[0443] R^(6a) is defined as

[0444] or R^(6a) is:

[0445] wherein R^(7a), R^(8a), Y², R^(9a), Q¹, W¹ are defined ashereinbefore;

[0446] Z is defined as

[0447] a) OR^(O);

[0448] c) N(R^(N2))R^(N1); or

[0449] g) NR^(N2)—SO₂—R^(C);

[0450] wherein R^(O) and R^(C) are optionally substituted with R⁶⁰; and

[0451] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1) and R^(N2), being optionally substituted with R⁶⁰; or

[0452] Z is N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) andR^(6b) is:

[0453] or R^(6b) is:

[0454] wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a),R^(8a), Y², R^(9a), W¹ respectively; and

[0455] Q² is aryl, Het, (C₁₋₆) alkyl-aryl, (C₁₋₆) alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which being optionallysubstituted with R⁶⁰

[0456] or Q² is R¹⁶⁰

[0457] or Q² is selected from the group consisting of O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of whichbeing optionally substituted with R¹⁶⁰;.

[0458] A third group of preferred compounds according to this inventionis defined by formula I.1c

[0459] wherein R^(c) is optionally substituted with R⁶⁰; and

[0460] Z is defined as

[0461] a) OR^(o);

[0462] c) N(R^(N2))R^(N1); or

[0463] g) NR^(N2)—SO₂—R^(c);

[0464] wherein R^(o) and R^(c) are optionally substituted with R⁶⁰; and

[0465] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1) and R^(N2), being optionally substituted with R⁶⁰; or

[0466] Z is N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) andR^(6b) is:

[0467] or R^(6b) is:

[0468] wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a),R^(8a), Y², R^(9a), W¹ respectively; and

[0469] Q² is aryl, Het, (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-Het,(C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which beingoptionally substituted with

[0470] R⁶⁰

[0471] or Q² is R¹⁶⁰

[0472] or Q² is selected from the group consisting of O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of whichbeing optionally substituted with R¹⁶⁰;.

[0473] A fourth group of preferred compounds according to this inventionis defined by formula I.1d

[0474] wherein

[0475] L is selected from OR^(c), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(c), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1) orN(R^(N1))OR^(o);

[0476] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1), R^(N2) and/or R^(N3), and R^(c) being optionally substitutedwith R⁶⁰;

[0477] Z is defined as

[0478] a) OR^(o);

[0479] c) N(R^(N2))R^(N1); or

[0480] g) NR^(N2)—SO₂—R^(c);

[0481] wherein R^(o) and R^(c) are optionally substituted with R⁶⁰; and

[0482] said R^(N1), including any heterocycle or heterobicycle formed byR^(N1) and R^(N2), being optionally substituted with R⁶⁰; or

[0483] Z is N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) andR^(6b) is:

[0484] or R^(6b) is

[0485] wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a),R^(8a), Y², R^(9a), W¹ respective; and

[0486] Q² is aryl, Het, (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-Het,(C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all of which beingoptionally substituted with R⁶⁰

[0487] or Q² is R¹⁶⁰

[0488] or Q² is selected from the group consisting of O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of whichbeing optionally substituted with R¹⁶⁰;

[0489] In the following, those preferred definitions of the groups L andZ which were described as preferred hereinbefore are formulated in moredetail.

[0490] L:

[0491] In the case Y⁰ is O, S or NR¹¹, L is more preferably

[0492] N(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(c), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—SO₂—R^(c) or N(R^(N1))OR^(o); wherein

[0493] R^(N2), R^(N3), R^(N4) are each independently H, methyl,(C₂₋₄)alkyl, (C₃₋₆)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all ofwhich being optionally substituted with C₁₋₃-alkyl, halogen, carboxy or(C₁₋₄)alkoxycarbonyl; and/or wherein said alkyl, cycloalkyl oralkyl-cycloalkyl, but preferably not the C-atom thereof directly bondedto the N-atom, is optionally substituted with hydroxy, amino,—NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂ and/or —O—(C₁₋₄-alkyl);

[0494] R^(N1) is H, methyl, (C₂₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, benzyl, (C₂₋₄)alkyl-phenyl, phenyl, Het or(C₁₋₄)alkyl-H t;

[0495] wherein all of said methyl, alkyl, and cycloalkyl groups areoptionally substituted with halogen, C₁₋₃-alkyl, carboxy or(C₁₋₄)alkoxycarbonyl, CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂; and/or

[0496] wherein all of said alkyl, and cycloalkyl groups, but preferablynot the C-atom thereof directly bonded to the N-atom, are optionallysubstituted with hydroxy, amino, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂ and/or—O—(C₁₋₄-alkyl); and

[0497] in the case

[0498] a) of a group N(R^(N2))R^(N1) the substituents R^(N1) and R^(N2)or

[0499] b) of a group NR^(N3)—N(R^(N2))R^(N1) the substituents R^(N1) andR^(N3) or R^(N1) and R^(N2) may be covalently bonded together to form a5-, 6- or 7-membered saturated or unsaturated heterocycle which may haveadditionally 1 or 2 heteroatoms or a 8-, 9-, 10- or 11-memberedsaturated or unsaturated heterobicycle which may have additionally from1, 2 or 3 heteroatoms, whereby the heteroatoms are selected from O, N,and S; and

[0500] wherein Het is a 4-, 5-, 6- or 7-membered, preferably 5- or6-membered, monocyclic group which contains 1 or 2 heteroatoms selectedfrom N, O and S, wherein a benzene ring may be fused to the monocyclicgroup; and

[0501] wherein said phenyl group, heterocycle, heterobicycle or Het isoptionally substituted by 1 to 4 substituents independently selectedfrom:

[0502] 1 to 3 substituents selected from halogen;

[0503] one of each substituent selected from: NO₂, cyano, azido; and

[0504] 1 to 3 substituents selected from: (C₁₋₄)alkyl, hydroxy,O—(C₁₋₄)alkyl, amino, —COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl),CON(C₁₋₄-alkyl)₂, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, N-pyrrolidinyl,N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, N-piperazinyl,—(C₁₋₄)alkyl-OH, —(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,—(C₁₋₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂,

[0505] wherein the alkyl-groups may be substituted with halogen; and

[0506] wherein the N-piperazinyl-group may be N-substituted withC₁₋₄-alkyl, (C₃₋₆)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl.

[0507] In the above described preferred case, wherein Y⁰ is O, S or NR¹¹and L is N(R^(N2))R^(N1) the substituents have most preferably thefollowing meanings:

[0508] R^(N2) is H, methyl, (C₂₋₄)alkyl, (C₃₋₆)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all of which being optionally substitutedwith C₁₋₃-alkyl, halogen, carboxy or (C₁₋₄)alkoxycarbonyl; and/orwherein said alkyl, cycloalkyl or alkyl-cycloalkyl, but preferably notthe C-atom thereof directly bonded to the N-atom, is optionallysubstituted with hydroxy, amino, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂ and/or—O—(C₁₋₄-alkyl);

[0509] R^(N1) is methyl, (C₂₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, benzyl, (C₂₋₄)alkyl-phenyl, Het and(C₁₋₄)alkyl-Het; wherein the methyl and alkyl groups are optionallysubstituted with C₁₋₃-alkyl, halogen, carboxy or (C₁₋₄)alkoxycarbonyl,CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂; and/or wherein said alkyl,but preferably not the C-atom thereof directly bonded to the N-atom, isoptionally substituted with hydroxy, amino, —NH(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)₂ and/or —O—(C₁₋₄-alkyl); and

[0510] wherein Het is a saturated or unsaturated 4-, 5-, 6- or7-membered, preferably 5- or 6-membered, monocyclic group which contains1 or 2 heteroatoms selected from N, O and S, wherein a benzene ring maybe fused to the monocyclic group; and

[0511] wherein said phenyl group, heterocycle, heterobicycle or Het isoptionally substituted by 1 to 4 substituents independently selectedfrom:

[0512] 1 to 3 substituents selected from halogen;

[0513] one of each substituent selected from: NO₂, cyano, azido; and

[0514] 1 to 3 substituents selected from: (C₁₋₄)alkyl, hydroxy,O—(C₁₋₄)alkyl, amino, —COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl),CON(C₁₋₄-alkyl)₂, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, N-pyrrolidinyl,N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, N-piperazinyl,—(C₁₋₄)alkyl-OH, —(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,—(C₁₋₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂,

[0515] wherein the alkyl-groups may be substituted with halogen; and

[0516] wherein the N-piperazinyl-group may be N-substituted withC₁₋₄-alkyl, (C₃₋₆)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl.

[0517] Both R^(N2) and R^(N1) may also be H, so that L is —NH₂.

[0518] According to the latter embodiment very preferred meanings forR^(N2) are selected from H, methyl, ethyl, n-propyl, i-propyl,cyclopropyl and cyclopropylmethyl; in particular H and methyl; and

[0519] R^(N1) is selected from methyl, ethyl, n-propyl, i-propyl,1-methylpropyl, 2-methylpropyl, (C₄₋₇)cycloalkyl,(C₄₋₇)cycloalkylmethyl-, (C₄₋₇)cycloalkylethyl-, (C₄₋₇)cycloalkenyl,(C₄₋₇)cycloalkenylmethyl-, (C₄₋₇)cycloalkenylethyl-, HCy-, HCy-methyl-,HCy-ethyl-, benzyl-, phenylethyl-, Hetaryl-methyl- and Hetaryl-ethyl-,

[0520] wherein

[0521] Hetaryl is an aromatic 5 or 6-membered monocyclic group whichcontains 1 or 2 heteroatoms selected from N, O and S; to which a benzenering may be fused; and

[0522] HCy is a 4-, 5-, 6- or 7-membered saturated or mono-unsaturatedheterocyclic group which contains 1 or 2 heteroatoms selected from N, O,S; and

[0523] wherein all (C₄₋₇)cycloalkyl, (C₄₋₇)cycloalkenyl, phenyl groups,Hetaryl and HCy are optionally substituted by 1 to 3 substituentsindependently selected from:

[0524] 1 to 3 substituents selected from fluorine;

[0525] one of each substituent selected from: chlorine, bromine, NO₂,cyano; and

[0526] 1 to 3 substituents selected from: methyl, ethyl, n-propyl,i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, C₁₋₃-alkoxy,—COOH, —COO(C₁₋₃)alkyl, CONH₂, CONH(C₁₋₃-alkyl), CON(C₁₋₃-alkyl)₂,amino, —NH(C₁₋₃-alkyl), —N(C₁₋₃-alkyl)₂; and

[0527] the C-atom in a-position to the N-atom (of the groupN(R^(N2))R^(N1)) is optionally substituted with methyl, CH₂OH, CH₂NH₂,CH₂NH(C₁₋₃-alkyl), CH₂N(C₁₋₃-alkyl)₂, carboxy, (C₁₋₃)alkoxycarbonyl,CONH₂, CONH(C₁₋₃-alkyl), CON(C₁₋₃-alkyl)₂; and/or, preferably or,

[0528] any C-atom in β-position to the N-atom (of the groupN(R^(N2))R^(N1)) is optionally substituted with hydroxy, C₁₋₃-alkoxy,amino, —NH(C₁₋₃-alkyl) or —N(C₁₋₃-alkyl)₂.

[0529] According to this preferred embodiment preferred examples of thegroup L are:

[0530] wherein each R is independently H, methyl, ethyl, n-propyl,i-propyl or cyclopropyl; most preferably H or methyl.

[0531] In the above described preferred case, wherein Y⁰ is O, S or NR¹¹and L is N(R^(N2))R^(N1) wherein R^(N2) and R^(N1) are covalently bondedtogether to form a heterocycle, the following meanings are mostpreferred:

[0532] R^(N2) and R^(N1) are covalently bonded together to form aheterocycle selected from azetidine, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, homopiperidine andhomopiperazine;

[0533] wherein said piperazine and homopiperazine may be N-substitutedwith C₁₋₄alkyl, (C₃₋₆)cycloalkyl or C₁₋₄alkyl-(C₃₋₆)cycloalkyl; and

[0534] wherein said heterocycles are optionally monosubstituted by(C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, HCy or C₁₋₃alkyl-HCy,wherein HCy is selected from azetidine, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, homopiperidine andhomopiperazine; and

[0535] wherein said heterocycles, including an optional alkyl-,cycloalkyl- or alkylcycloalkyl-group and/or HCy or C₁₋₃alkyl-HCy group,are optionally substituted by 1 to 4 substituents independently selectedfrom:

[0536] 1 to 3 substituents selected from halogen and (C₁₋₄)alkyl;

[0537] one of each substituent selected from: NO₂, cyano, azido; and

[0538] 1 or 2 substituents selected from: hydroxy, O—(C₁₋₄)alkyl, amino,—COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —(C₁₋₄)alkyl-OH,—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,—(C₁₋₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂;

[0539] wherein said alkyl-groups may be substituted with halogen.

[0540] According to this preferred embodiment preferred examples of thegroup L are:

[0541] wherein each R is independently H, methyl, ethyl, n-propyl,i-propyl or cyclopropyl; most preferably H or methyl.

[0542] According to another preferred embodiment wherein Y⁰ is O and Lis OR^(6a), or wherein Y⁰ is O or S and L is N(R^(5a))R^(6a), whereinR^(5a) is defined as R^(N2), and

[0543] R^(6a) is defined according to the following subformula:

[0544] wherein

[0545] R^(7a) is defined as H, COOH, CONH₂, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₄)alkyl-aryl, (C₁₋₄)alkyl-Het; all of which are optionallysubstituted with R⁶⁰; and

[0546] R⁸a is H or (C₁₋₄)alkyl; or

[0547] R^(7a) and R^(8a) are covalently bonded together to form a(C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3heteroatom selected from O, N, and S; and

[0548] when L is N(R^(5a))R^(6a), either of R^(7a) or R^(8a) may becovalently bonded to R^(5a) to form a nitrogen-containing 5-or6-membered heterocycle, wherein said cycloalkyl or heterocycle beingoptionally substituted by R¹⁵⁰; and

[0549] W¹ is selected from

[0550] a) a single bond;

[0551] b) —CH₂—;

[0552] c) —CH₂—CH₂—; and

[0553] d) —CH═CH—;

[0554] wherein the alkylene and alkenylene groups according to b), c)and d) may be substituted with (C₁₋₃) alkyl;

[0555] Q¹ is a group of the subformula IIIa

[0556] wherein

[0557] Q^(1a) is aryl, Hetaryl, (C₁₋₃) alkyl-aryl or(C₁₋₃)alkyl-Hetaryl;

[0558] Q^(1b) is phenyl or Hetaryl;

[0559] Q^(1c) is a bond, O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl,C₂₋₄-alkenyl or C₂₋₄-alkynyl; and

[0560] R^(1q) is selected from H, CN, COOR¹⁶¹, CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂,—N(R¹⁶²)₂, OR¹⁶¹, SR¹⁶¹, —NHCOR¹⁶², —NH—CO—COOR¹⁶¹, —NH—CO—CON(R¹⁶²)₂,NHSO₂R^(c), CONHSO₂R^(c), SO₂NHCOR^(c), tetrazole, triazole andCONHSO₂N(R¹⁶²)₂;

[0561] q is 0 or 1;

[0562] wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/oralkynyl-groups is optionally substituted with R¹⁶⁰; and

[0563] wherein Hetaryl is an aromatic 5- or 6-membered heterocyclehaving 1 or 2 heteroatoms selected from O, N, and S, or a 8-, 9- or10-membered aromatic heterobicycle having 1 to 4 heteroatoms selectedfrom O, N, and S.

[0564] In another above described preferred case, wherein Y⁰ is O and Lis OR^(6a), or wherein Y⁰ is O or S and L is N(R^(5a))R^(6a) whereinR^(5a) is defined as R^(N2), and

[0565] R^(6a) is defined as:

[0566] the substituents have most preferably one of the followingmeanings:

[0567] R^(7a) and R^(8a) are each independently defined as R^(o),wherein said R^(o) is optionally substituted with R⁶⁰; or

[0568] R^(7a) and R^(8a) are covalently bonded together to form a second(C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3heteroatom selected from O, N, and S; and when L is N(R^(5a))R^(6a),either of R^(7a) or R^(8a) may be covalently bonded to R^(5a) to form anitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkylor heterocycle being optionally substituted by R¹⁵⁰; and

[0569] Y² is O or S;

[0570] R^(9a) is defined as R^(o), wherein said R^(o) is optionallysubstituted with R⁶⁰; or

[0571] R^(9a) is covalently bonded to either of R^(7a) or R^(8a) to forma 5- or 6-membered heterocycle;

[0572] Q¹ is a group of the subformula IIIa

[0573] wherein

[0574] Q^(1a) is aryl, Hetaryl, (C₁₋₃) alkyl-aryl or(C₁₋₃)alkyl-Hetaryl;

[0575] Q^(1b) is phenyl or Hetaryl;

[0576] Q^(1c) is a bond, O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl,C₂₋₄-alkenyl or C₂₋₄-alkynyl; and

[0577] R^(1q) is selected from H, CN, COOR¹⁶¹, CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂,—N(R¹⁶²)₂, OR¹⁶¹, SR¹⁶¹, —NHCOR¹⁶², —NH—CO—COOR¹⁶¹, —NH—CO—CON(R¹⁶²)₂,NHSO₂R^(c), CONHSO₂R^(c), SO₂NHCOR^(c), tetrazole, triazole andCONHSO₂N(R¹⁶²)₂;

[0578] q is 0 or 1;

[0579] wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/oralkynyl-groups is optionally substituted with R¹⁶⁰; and

[0580] wherein Hetaryl is an aromatic 5- or 6-membered heterocyclehaving 1 or 2 heteroatoms selected from O, N, and S, or a 8-, 9- or10-membered aromatic heterobicycle having 1 to 4 heteroatoms selectedfrom O, N, and S.

[0581] Z:

[0582] According to one preferred embodiment Z is defined as OR^(o),wherein R^(o) is optionally substituted with R⁶⁰.

[0583] In this embodiment wherein Z is OR^(o) the preferred meaning of

[0584] R^(o) is H, C₁₋₄alkyl, (C₃₋₆)cycloalkyl,C₁₋₃alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, (C₁₋₃alkyl)phenyl,(C₁₋₃)alkyl-pyridinyl, wherein said alkyl, alkyl-cycloalkyl, cycloalkyl,alkenyl, alkyl-phenyl or alkyl-pyridinyl is optionally substituted with1 to 3 substituents independently selected from:

[0585] 1, 2 or 3 fluorine substituents; and

[0586] one of each substituent selected from chlorine, bromine, iodine,CN, nitro, C₁₋₄alkyl, CF₃, COOR¹⁶¹, SO₂R¹⁶¹, OR¹⁶¹, N(R¹⁶²)₂,SO₂N(R¹⁶²)₂, NR¹⁶²COR¹⁶² or CON(R¹⁶²)₂, wherein R¹⁶¹ and each R¹⁶² isindependently H, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R¹⁶² are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle.

[0587] A most preferred meaning of Z according to this embodiment is OH.

[0588] According to another preferred embodiment Z is defined asN(R^(N2))R^(N1) wherein R^(N1), including any heterocycle orheterobicycle formed by R^(N1) and R^(N2), is optionally substitutedwith R⁶⁰.

[0589] Preferred meanings of R^(N1) and R^(N2) in this embodiment are:

[0590] R^(N2) is H, methyl, (C₂₋₄)alkyl, (C₃₋₆)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all of which being optionally substitutedwith C₁₋₃-alkyl, halogen, carboxy or (C₁₋₄)alkoxycarbonyl; and/orwherein said alkyl, cycloalkyl or alkyl-cycloalkyl, but preferably notthe C-atom thereof directly bonded to the N-atom, is optionallysubstituted with hydroxy, amino, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂ and/or—O—(C₁₋₄-alkyl); whereby R^(N2) is most preferably H; and

[0591] R^(N1) is methyl, (C₂₋₆)alkyl, (C₁₋₄)alkyl-phenyl or(C₁₋₄)alkyl-H t; wherein all of the methyl and alkyl groups areoptionally substituted with C₁₋₃-alkyl, halogen, carboxy or(C₁₋₄)alkoxycarbonyl, CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂;

[0592] and/or wherein said alkyl, but preferably not the C-atom thereofdirectly bonded to the N-atom, is optionally substituted with hydroxy,amino, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂ and/or —O—(C₁₋₄-alkyl); and

[0593] wherein Het is a 4-, 5-, 6- or 7-membered, preferably 5- or6-membered, monocyclic group which contains 1 or 2 heteroatoms selectedfrom N, O and S, wherein a benzene ring may be fused to the monocyclicgroup; and

[0594] wherein said phenyl group, heterocycle, heterobicycle or Het isoptionally substituted by 1 to 4 substituents independently selectedfrom:

[0595] 1 to 3 substituents selected from halogen;

[0596] one of each substituent selected from: NO₂, cyano, azido; and

[0597] 1 to 3 substituents selected from: (C₁₋₄)alkyl, hydroxy,O—(C₁₋₄)alkyl, amino, —COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl),CON(C₁₋₄-alkyl)₂, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, N-pyrrolidinyl,N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, N-piperazinyl,—(C₁₋₄)alkyl-OH, —(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,-(C₁₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂,

[0598] wherein the alkyl-groups may be substituted with halogen; and

[0599] wherein the N-piperazinyl-group may be N-substituted withC₁₋₄-alkyl, C₃₋₄-cycloalkyl or C₁₋₃-alkyl-C₃₋₆-cycloalkyl.

[0600] Most preferred meanings of R^(N1) and R^(N2) in this embodimentwherein Z is defined as N(R^(N2))R^(N1) are:

[0601] R^(N2) is H, methyl, ethyl, n-propyl, i-propyl, all of whichbeing optionally substituted with methyl, fluorine, chlorine, carboxylor methoxycarbonyl; and/or wherein said ethyl, n-propyl or i-propyl, butpreferably not the C-atom thereof directly bonded to the N-atom, isoptionally substituted with hydroxy, amino, —NH(CH₃), —N(CH₃)₂ and/or—O—(CH₃);

[0602] R^(N1) is methyl, ethyl, n-propyl, i-propyl, benzyl, phenylethyl,pyridinylmethyl or pyridinylethyl; wherein said methyl, ethyl, n-propyl,and i-propyl, groups are optionally substituted with fluorine, chlorine,methyl, ethyl, n-propyl, i-propyl, carboxy, methoxycarbonyl, CONH₂,CONH(CH₃), CON(CH₃)₂; and/or

[0603] wherein said ethyl, n-propyl or i-propyl, but preferably not theC-atom thereof directly bonded to the N-atom, is optionally substitutedwith hydroxy, amino, —NH(CH₃), —N(CH₃)₂ and/or —O—CH₃; and

[0604] wherein said phenyl and pyridinyl group is optionally substitutedby 1, 2 or 3 substituents independently selected from:

[0605] 1, 2 or 3 substituents selected from halogen;

[0606] one of each substituent selected from: NO₂, cyano, azido; and

[0607] 1, 2 or 3 substituents selected from: methyl, trifluoromethyl,ethyl, n-propyl, i-propyl, hydroxy, methoxy, ethoxy, —COOH, —COOCH₃,CONH₂, CONH(CH₃), CON(CH₃)₂, amino, —NH(CH₃), —N(CH₃)₂, —CH₂—OH,—CH₂—O—CH₃, —CH₂—NH₂, —CH₂—N(CH₃)₂ and —(CH₂)₂—OH.

[0608] In the latter embodiment R^(N2) is preferably H, methyl or ethyl,most preferably H, and R^(N1) is preferably benzyl or phenylethyl, bothof which are optionally substituted with methyl, ethyl, n-propyl,i-propyl, fluorine, chlorine, carboxy, methoxycarbonyl, CONH₂,CONH(CH₃), CON(CH₃)₂; and which at the phenyl group is optionallysubstituted with 1, 2 or 3 substituents independently selected from:

[0609] 1, 2 or 3 substituents selected from halogen;

[0610] one of each substituent selected from: NO₂, cyano, azido; and

[0611] 1, 2 or 3 substituents selected from: methyl, trifluoromethyl,ethyl, n-propyl, i-propyl, hydroxy, methoxy, ethoxy, —COOH, —COOCH₃,CONH₂, CONH(CH₃), CON(CH₃)₂, amino, —NH(CH₃), —N(CH₃)₂, —CH₂—OH,—CH₂—O—CH₃, —CH₂—NH₂, —CH₂—N(CH₃)₂ and —(CH₂)₂—OH.

[0612] Therefore most preferred meanings of Z according to thisembodiment are:

[0613] wherein those groups wherein the phenyl is substituted twice withOMe and/or OH are the very most preferred ones.

[0614] According to another preferred embodiment Z is defined asNR^(N2)—SO₂—R^(c) or NR^(N2)—CO—R^(c) wherein R^(N2) and R^(c) arepreferably defined as follows:

[0615] R^(N2) is H, (C₁₋₄)alkyl, (C₃₋₄)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl; in particular H; and

[0616] R^(c) is (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, phenyl, naphthyl, Het,(C₁₋₃)alkyl-phenyl, (C₁₋₃)alkyl-naphthyl, (C₁₋₃)alkyl-Het, wherein saidalkyl, cycloalkyl, alkyl-cycloalkyl, alkenyl, phenyl, naphthyl, Het,alkyl-phenyl, alkyl-naphthyl, or alkyl-Het, are all optionallysubstituted with 1 to 4 substituents selected from R⁶⁰.

[0617] In this embodiment the preferred meaning of R^(c) is methyl,ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, pyrrolidine,piperidine, morpholine, thiomorpholine, piperazine, phenyl, naphthyl,benzyl, thiophene, furan, pyrrole, imidazole, pyrazole, oxazole,isoxazole, thiazole, pyridazine, pyrimidine, pyrazine, diazepine,azepine, quinoline, isoquinoline, benzofuran, benzothiophene,benzothiazole, purine, pteridine, 2,1,3-benzothiadiazole

[0618] and imidazo[2,1-B][1,3]thiazole

[0619] all of which are optionally substituted with 1 to 3 substituentsselected from R⁶⁰, particularly OH, CN, halogen, nitro, (C₁₋₃)alkyl,O(C₁₋₃)alkyl, carboxyl, COO(C₁₋₃)alkyl, amino, NH(C₁₋₃)alkyl,N((C₁₋₃)alkyl)₂, NHCO(C₁₋₃)alkyl, wherein the alkyl groups may besubstituted by halogen.

[0620] According to another preferred embodiment wherein Z is OR^(6b) orN(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) and R^(6b) is:

[0621] wherein

[0622] R^(7b) is defined as H, COOH, CONH₂, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₄)alkyl-aryl, (C₁₋₄)alkyl-Het; all of which are optionallysubstituted with R⁶⁰; and

[0623] R^(8b) is H or (C₁₋₄)alkyl; or

[0624] R^(7b) and R^(8b) are covalently bonded together to form a second(C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3heteroatom selected from O, N, and S; and when Z is N(R^(5b))R^(6b),either of R^(7b) or R^(8b) may be covalently bonded to R^(5b) to form anitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkylor heterocycle being optionally substituted by R¹⁵⁰; and

[0625] W² is selected from

[0626] a) a single bond;

[0627] b) —CH₂—;

[0628] c) —CH₂—CH₂—; and

[0629] d) —CH═CH—;

[0630] wherein the alkylene and alkenylene groups according to b), c)and d) may be substituted with (C₁₋₃) alkyl;

[0631] Q² is a group of the subformula IIIb

[0632] wherein

[0633] Q^(2a) is aryl, Hetaryl, (C₁₋₃)alkyl-aryl or (C₁₋₃)alkyl-Hetaryl;

[0634] Q^(2b) is phenyl or Hetaryl;

[0635] Q^(2c) is a bond, O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl,C₂₋₄-alkenyl or C₂₋₄-alkynyl, wherein said O—C₁₋₄-alkyl, S—C₁₋₄-alkyl,C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl are optionally substituted withR¹⁷⁰;

[0636] wherein R¹⁷⁰ is defined as H or as 1, 2 or 3 substituentsindependently selected from:

[0637] 1, 2, or 3 substituents selected from halogen;

[0638] one or two of each substituent selected from (C₁₋₄)alkyl,(C₁₋₄)alkoxy, (C₃₋₅)cycloalkyl, or cyano; wherein (C₁₋₄)alkyl mayoptionally be substituted with 1 to 3 halogen atoms; and

[0639] R^(2q) is selected from H, CN, COOR¹⁶¹, CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂,—N(R¹⁶²)₂, OR¹⁶¹, SR¹⁶¹, —NHCOR¹⁶², —NH—CO—COOR¹⁶¹, —NH—CO—CON(R¹⁶²)₂,NHSO₂R^(c), CONHSO₂R^(c), SO₂NHCOR^(c), tetrazole, triazole andCONHSO₂N(R¹⁶²)₂;

[0640] qa is 0 or 1;

[0641] qb is 0 or1;

[0642] wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/oralkynyl-groups is optionally substituted with R¹⁶⁰; and

[0643] wherein Hetaryl is an aromatic 5- or 6-membered heterocyclehaving 1 or 2 heteroatoms selected from O, N, and S, or a 9- or10-membered aromatic heterobicycle having 1 to 4 heteroatoms selectedfrom O, N, and S.

[0644] Most preferably the index qa is 1.

[0645] In another above described preferred case, wherein Z is OR^(6b)or N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) and R^(6b) is:

[0646] the substituents have most preferably one of the followingmeanings:

[0647] R^(7b) and R^(8b) are each independently defined as R^(o),wherein said R^(o) is optionally substituted with R⁶⁰; or

[0648] R^(7b) and R^(8b) are covalently bonded together to form a(C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3heteroatom selected from O, N, and S;

[0649] or when Z is N(R^(5b))R^(6b), either of R^(7b) or R^(8b) may becovalently bonded to R^(5b) to form a nitrogen-containing 5-or6-membered heterocycle, wherein said cycloalkyl or heterocycle beingoptionally substituted by R¹⁵⁰; and

[0650] Y³ is O or S;

[0651] R^(9b) is defined as R^(o), wherein said R^(o) is optionallysubstituted with R⁶⁰; or

[0652] R^(9b) is covalently bonded to either of R^(7b) or R^(8b) to forma 5- or 6-membered heterocycle;

[0653] Q² is a group of the subformula IIIb

[0654] wherein

[0655] Q^(2a) is aryl, Hetaryl, (C₁₋₃) alkyl-aryl or(C₁₋₃)alkyl-Hetaryl;

[0656] Q^(2b) is a phenyl or Hetaryl;

[0657] Q^(2c) is a bond, O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl,C₂₋₄-alkenyl or C₂₋₄-alkynyl, wherein said O—C₁₋₄-alkyl, S—C₁₋₄-alkyl,C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl are optionally substituted withR¹⁷⁰

[0658] wherein R¹⁷⁰ is defined as H or as 1, 2 or 3 substituentsindependently selected from:

[0659] 1, 2, or 3 substituents selected from halogen;

[0660] one or two of each substituent selected from (C₁₋₄) alkyl, (C₁₋₄)alkoxy, (C₃₋₅) cycloalkyl, or cyano; wherein (C₁₋₄) alkyl may optionallybe substituted with 1 to 3 halogen atoms; and

[0661] R^(2q) is selected from H, CN, COOR¹⁶¹, CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂,—N(R¹⁶²)₂, OR¹⁶¹, SR¹⁶¹, —NHCOR¹⁶², —NH—CO—COOR¹⁶¹, —NH—CO—CON(R¹⁶²)₂,NHSO₂R^(c), CONHSO₂R^(c), SO₂NHCOR^(c), tetrazole, triazole andCONHSO₂N(R¹⁶²)₂;

[0662] qa is 0 or 1;

[0663] qb is 0 or 1;

[0664] wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/oralkynyl-groups is optionally substituted with R¹⁶⁰; and

[0665] wherein Hetaryl is an aromatic 5- or 6-membered heterocyclehaving 1 or 2 heteroatoms selected from O, N, and S, or a 9- or10-membered aromatic heterobicycle having 1 to 4 heteroatoms selectedfrom O, N, and S.

[0666] Most preferably the index qa is 1.

[0667] Hereinafter, preferred groups and substituents are described forthose cases wherein either L or Z, or both L and Z are defined asfollows:

[0668] L is OR^(6a) or N(R^(N2))R^(6a) wherein R^(6a) is:

[0669] Z is OR^(6b) or N(R^(N2))R^(6b) wherein R^(6b) is:

[0670] wherein Q¹ is defined as

[0671] wherein Q² is defined as

[0672] Most preferably one of W¹ and W² or both W¹ and W² represent asingle bond.

[0673] Preferred meanings of one of R^(7a) and R^(7b) or both R^(7a) andR^(7b) are H, COOH, CONH₂, CF₃, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₃)alkyl-(C₃₋ ₇)cycloalkyl, Hetaryl or (C₁₋₃)alkyl-Hetaryl, whereinthe alkyl, cycloalkyl groups and Hetaryl groups are optionallysubsituted with R¹⁶⁰.

[0674] Preferred meanings of one of R^(8a) and R^(8b) or both R^(8a) andR^(8b) are H and CH₃.

[0675] Furthermore, it is preferred that R^(7a) and R^(8a) and/or R^(7b)and R^(8b) are covalently bonded together to form a second(C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 2heteroatom selected from O, N, and S, wherein said cycloalkyl orheterocycle being optionally substituted with R¹⁶⁰, preferably with 1 to3 substituents selected from hydroxy, (C₁₋₃)alkyl, CO(C₁₋₃)alkyl andSO₂(C₁₋₃)alkyl.

[0676] According to the hereinbefore described embodiment R^(7a) andR^(7b) is each independently preferably selected from COOH, CONH₂,methyl, ethyl, n-propyl, i-propyl, 2-methylpropyl, hydroxy-methyl,1-hydroxy-ethyl, amino-methyl, 1-amino-ethyl, 2-hydroxy-ethyl,2-methylthio-ethyl, 2-amino-ethyl, 2-(dimethylamino)-ethyl andthiazolyl, wherein the thiazolyl group is optionally substituted withR¹⁶⁰; or

[0677] R^(7b) and R^(8b) are covalently bonded together to form a cyclicgroup preferably selected from:

[0678] Most preferably, the groups CR^(7a)R^(8a) and CR^(7b)R^(8b) areindependently selected from:

[0679] R^(9a) and/or R^(9b) is preferably H, (C₁₋₃ alkyl),(C₃₋₆)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all of whichoptionally substituted with 1 to 3 substituents selected from halogen,hydroxy and methyl; most preferably R^(9a) and/or R^(9b) is H or methyl.

[0680] Preferably Q^(1a) and Q^(2a) are independently selected from

[0681] wherein 1 or 2 C-atoms of each cyclic group as listed above maybe substituted with R¹⁶⁰;

[0682] R^(L) is H, (C₁₋₄alkyl) or (C₁₋₄)alkoxy, and

[0683] R^(Q) is H or CH₃, (C₂₋₆alkyl), —CH₂—(C₂₋₆alkenyl),—CH₂—(C₂₋₆alkynyl), (C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; allof which being optionally substituted with C₁₋₆-alkyl, halogen, carboxyor C₁₋₆-alkoxycarbonyl; and/or wherein said alkyl, cycloalkyl oralkylcycloalkyl, but preferably not the C-atom thereof directly bondedto the N-atom, is optionally substituted with hydroxy, C₁₋₆alkoxy,amino, —NH(C₁₋₄-alkyl) and/or —N(C₁₋₄-alkyl)₂;

[0684] Preferably Q^(1b) and/or Q^(2b) are selected from the groupconsisting of phenyl, furan, thiophene, oxazole, thiazole, pyridine,pyrimidine, pyrrazole, imidazole and pyrazine.

[0685] Most preferably Q^(1b) and Q^(2b) are independently selected fromthe group consisting of

[0686] wherein all shown cyclic groups are optionally substituted withR¹⁶⁰.

[0687] Q^(1c) and Q^(2c) are preferably selected from a bond, —O—CH₂—,—CH₂—CH₂—, —C(R¹⁷⁰)═CH— and —CH═C(R¹⁷⁰)—;

[0688] most preferably selected from a bond and —CH═C(R¹⁷⁰)—,

[0689] wherein R¹⁷⁰ is preferably selected from H, F, —CH₃, —CH₂CH₃,—CF₃ and cyclopropyl;

[0690] most preferably selected from H, F, —CH₃ and —CH₂CH₃.

[0691] R^(1q) and R^(2q) are preferably selected from H, CN, COOR¹⁶¹,CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂, —N(R¹⁶²)₂, OR¹⁶¹—NHCOR¹⁶², —NH—CO—COOR¹⁶¹,—NH—CO—CON(R¹⁶²)₂, NHSO₂R^(c), CONHSO₂R^(c), SO₂NHCOR^(c), tetrazole,triazole and CONHSO₂N(R¹⁶²)₂;

[0692] most preferably selected from COOR¹⁶¹, CON(R¹⁶²)₂ andSO₂N(R¹⁶²)₂;

[0693] wherein R¹⁶¹ and R¹⁶² are as defined, but most preferably Hand/or methyl.

[0694] In the case of L comprising the group Q¹ as defined hereinbefore,especially preferred compounds obey one of the following conditions

[0695] a) Q^(1a) is phenyl, q is 1 and Q^(1c) is a bond;

[0696] b) Q^(1a) is phenyl, q is 0 and Q^(1c) is vinyl; or

[0697] c) Q^(1a) is a 9- or 10-membered aromatic heterobicycle having 1or 2 heteroatoms selected from O, N, and S, said heterobicycleoptionally being substituted with R¹⁶⁰; q is 0 and Q^(1c) is a bond,—CH₂—CH₂— or —CH═CH—.

[0698] Furthermore, those compounds of the above described embodimentare especially preferred wherein the group Q^(1c)—R^(1q) is —CH═CH—COOH.

[0699] In the case of Z comprising the group Q² as defined hereinbefore,especially preferred compounds obey one of the following conditions:

[0700] a) qa is 1, Q^(2a) is phenyl, qb is 1 and Q^(2c) is a bond;

[0701] b) qa is 1, Q^(2a) is phenyl, qb is 0 and Q^(2c) is —CH═C(R¹⁷⁰)—,wherein R¹⁷⁰ is selected from H, F, —CH₃ or —CH₂CH₃; or

[0702] c) qa is 1, Q^(2a) is a 9- or 10-membered aromatic heterobicyclehaving 1 or 2 heteroatoms selected from O, N, and S, said heterobicycleoptionally being substituted with R¹⁶⁰; qb is 0 and Q^(2c) is a bond,—CH₂—CH₂— or —CH═C(R¹⁷⁰)—, wherein R¹⁷⁰ is selected from H, F, —CH₃ or—CH₂CH₃.

[0703] Furthermore, those compounds of the above described embodimentare especially preferred wherein the group Q^(2c)—R^(2q) is—CH═C(R¹⁷⁰)—COOH, wherein R¹⁷⁰ is selected from H, F, —CH₃ or —CH₂CH₃.

[0704] Preferably Q¹ and Q² are independently selected from:

[0705] wherein all shown cyclic groups are optionally substituted withR¹⁶⁰; most preferably 1 or 2 substituents selected from fluorine,chlorine, bromine, OH, methoxy, ethoxy, amino, NH(CH₃), methyl, ethyl,i-propyl and n-propyl;

[0706] wherein R¹⁷⁰ is each independently defined as hereinbefore;preferably R¹⁷⁰ is defined as H, F, —CH₃, —CH₂CH₃, —CF₃, or cyclopropyl;most preferably H, F, —CH₃, or —CH₂CH₃; and

[0707] wherein R^(Q) is each independently defined as hereinbefore;preferably R^(Q) is defined as H, (C₁₋₆-alkyl), (C₃₋₆)cycloalkyl or(C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; most preferably H or methyl.

[0708] Most preferably, Q¹ and Q² are independently selected from:

[0709] wherein all shown cyclic groups are optionally substituted withR¹⁶⁰; most preferably 1 or 2 substituents selected from fluorine,chlorine, bromine, OH, methoxy, ethoxy, amino, NH(CH₃), methyl, ethyl,i-propyl and n-propyl;

[0710] wherein R¹⁷⁰ is each independently defined as hereinbefore;preferably R¹⁷⁰ is defined as H, F, —CH₃, —CH₂CH₃, —CF₃, or cyclopropyl; most preferably H, F, —CH₃, or —CH₂CH₃; and

[0711] wherein R^(Q) is each independently defined as hereinbefore;preferably R^(Q) is defined as H, (C₁₋₆alkyl), (C₃₋₆)cycloalkyl or(C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; most preferably H or methyl.

[0712] In case Q^(1a) or Q^(2a), is a phenylene or Hetaryl group,preferred substituents of this group are selected from (C₁₋₃)alkyl and(C₁₋₃)alkoxy, especially from methyl, ethyl, methoxy, ethoxy. In thecase where Q^(1a) or Q^(2a) is phenylene, the subsituent is preferablyin meta-position to Q^(1b), in case q=1, or to Q^(2b), in case qb=1; orto Q^(1c), in case q=0, or to Q^(2c), in case qb=0, respectively. Thus,most preferred groups Q¹ and Q² which are substituted are for example:

[0713] wherein R¹⁷⁰ is each independently defined as hereinbefore;preferably R¹⁷⁰ is defined as H, F, —CH₃, —CH₂CH₃, —CF₃, or cyclopropyl; most preferably H, F, —CH₃, or —CH₂CH₃;.

[0714] Hereinafter preferred groups N(R^(5a))R^(6a) and N(R^(5b))R^(6b)are described for those cases wherein either L or Z, or both L and Z aredefined as follows:

[0715] L is N(R^(5a))R^(6a) wherein R^(6a), is

[0716] Z is N(R^(5b))R^(6b) wherein R^(6b) is:

[0717] Therefore, according to this embodiment examples of verypreferred groups L and Z, in case qa is 1, are independently selectedfrom the group consisting of:

[0718] wherein all shown cyclic groups are optionally substituted withR¹⁶⁰; most preferably 1 or 2 substituents selected from fluorine,chlorine, bromine, OH, methoxy, ethoxy, amino, NH(CH₃), methyl, ethyl,i-propyl and n-propyl;

[0719] wherein R¹⁷⁰ is each independently defined as hereinbefore;preferably R¹⁷⁰ is defined as H, F, —CH₃, —CH₂CH₃, —CF₃, or cyclopropyl; most preferably H, F, —CH₃, or —CH₂CH₃; and

[0720] wherein R^(Q) is each independently defined as hereinbefore;preferably R^(Q) is defined as H, (C₁₋₆-alkyl), (C₃₋₆)cycloalkyl or(C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; most preferably H or methyl.

[0721] Examples of preferred groups Z, in case qa is 0, areindependently selected from the group consisting of:

[0722] Hereinafter, preferred groups N(R^(8a))R^(6a) and N(R^(5b))R^(6b)are described for those cases wherein either L or Z, or both L and Z aredefined as follows:

[0723] L is N(R^(5a))R^(6a) wherein R^(6a) is:

[0724] Z is N(R^(5b))R^(6b) wherein R^(6b) is:

[0725] Therefore, according to this embodiment L and Z are morepreferably independently selected from the group consisting of:

[0726] wherein all shown cyclic groups are optionally substituted withR¹⁶⁰; most preferably 1 or 2 substituents selected from fluorine,chlorine, bromine, OH, methoxy, ethoxy, amino, NH(CH₃), methyl, ethyl,i-propyl and n-propyl;

[0727] wherein R¹⁷⁰ is each independently defined as hereinbefore;preferably R¹⁷⁰ is defined as H, F, —CH₃, —CH₂CH₃, —CF₃, or cyclopropyl;most preferably H, F, —CH₃, or —CH₂CH₃; and

[0728] wherein R^(Q) is each independently defined as hereinbefore;preferably R^(Q) is defined as H, (C₁₋₆-alkyl), (C₃₋₆)cycloalkyl or(C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; most preferably H or methyl.

[0729] R²:

[0730] Preferably R² is R²¹, wherein R²¹ is a phenyl or Het selectedfrom the group of formulas

[0731] and wherein said R²¹ is optionally substituted with R¹⁵⁰.

[0732] A very most preferred definition of R² is

[0733] all of which may be unsubstituted or substituted as defined.

[0734] In the case R² as defined above is substituted, it is preferablysubstituted with 1, 2 or 3 substituents selected from:

[0735] 1 to 3 substituents selected from halogen;

[0736] one of each substituent selected from: NO₂, cyano, azido; and

[0737] 1 to 2 substituents selected from:

[0738] a) (C₁₋₄)alkyl or (C₁₋₄)alkoxy, both optionally substituted withOH, O(C₁₋₄)alkyl, SO₂(C₁₋₄alkyl); 1 to 3 halogen atoms, amino, NH(CH₃)or N(CH₃)₂);

[0739] b) NR¹¹¹R¹¹² wherein both R¹¹¹ and R¹¹² are independently H,(C₁₋₄)alkyl, or R¹¹² is (C₃₋₇)cycloalkyl, (C₁₋₃)alkyl(C₃₋₇)cycloalkyl,phenyl, benzyl; or both R¹¹¹ and R¹¹² are covalently bonded together andto the nitrogen to which they are attached to form a nitrogen-containingheterocycle, each of said alkyl, cycloalkyl, alkylcycloalkyl, phenyl andbenzyl, being optionally substituted with halogen or: —OR^(2h) orN(R^(2h))₂, wherein each R^(2h) is independently H, (C₁₋₄)alkyl, or bothR^(2h) are covalently bonded together and to the nitrogen to which theyare attached to form a nitrogen-containing heterocycle;

[0740] c) NHCOR¹¹⁷ wherein R¹¹⁷ is (C₁₋₄)alkyl, O(C₁₋₄)alkyl orO(C₃₋₇)cycloalkyl; and

[0741] e) CONH₂, CONH(C₁₋₄alkyl), CON(C₁₋₄alkyl)₂.

[0742] Most preferred substituents of R² are selected from:

[0743] 1 to 2 substituents selected from fluorine;

[0744] one of each substituent selected from: chlorine, bromine, NO₂,cyano; and

[0745] 1 to 2 substituents selected from:

[0746] a) methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, methoxy,trifluoromethoxy, ethoxy, n-propoxy or i-propoxy, wherein said methyl,ethyl, n-propyl, i-propyl, ethoxy, n-propoxy and i-propoxy areoptionally substituted with OH, methoxy, amino, NH(CH₃) or N(CH₃)₂;

[0747] b) NR¹¹¹R¹¹² wherein both R¹¹¹ and R¹¹² are independently H ormethyl, or R¹¹² is phenyl or benzyl;

[0748] c) NHCOR¹¹⁷ wherein R¹¹⁷ is methyl or methoxy; and

[0749] e) CONH₂, CONH(CH₃), CON(CH₃)₂.

[0750] R³:

[0751] R³ is preferably selected from (C₃₋₇)cycloalkyl,(C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl, (C₆₋₁₀)bicycloalkenyl, or HCywherein said groups are unsubstituted or mono- or disubstituted byhalogen, hydroxy, C₁₋₄alkyl and/or O—C₁₋₄alkyl, wherein the alkyl groupsmay be fluorinated.

[0752] Most preferably R³ is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, or a group selected from:

[0753] wherein all said cyclic groups are unsubstituted or substitutedby fluorine, C₁₋₃alkyl or CF₃.

[0754] The very most preferred meaning of R³ is cyclopentyl, orcyclohexyl.

[0755] R^(4a), R^(4b), R⁵:

[0756] Preferably R^(4a), R^(4b), R⁵ each are independently H, hydroxy,halogen, cyano, nitro, carboxyl, (C₁₋₄)alkyl, CF₃, (C₁₋₄)alkoxy,—O—(C₃₋₇)cycloalkyl, —O—(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, —O-aryl,—O—(C₁₋₃)alkyl-aryl, —O-Het, —O—(C₁₋₃)alkyl-Het, NR^(N1)R^(N2), orCOR^(o), NR^(N2)COR^(c), CONR^(N2)R^(N1), NR^(N3)CONR^(N1)R^(N2), inparticular NHCO(C₁₋₄)alkyl or CONHR^(N1), NHCONHR^(N1);

[0757] wherein R^(o), R^(N1), R^(N2), R^(N3) are as defined; preferablyR^(o), R^(N1) are independently of each other H, (C₁₋₄)alkyl, aryl,(C₁₋₃)alkyl-aryl, wherein aryl is preferably optionally substitutedphenyl; and preferably R^(N2), R^(N3) are H or methyl; wherein all saidalkyl groups, including alkoxy, may be mono-, di- or trisubstituted byfluorine or mono-substituted by chlorine or bromine.

[0758] Most preferred substituents R^(4a), R^(4b), R⁵ each areindependently H, hydroxy, halogen, cyano, nitro, methyl, CF₃, methoxy,carboxy, amino, —NMe₂, —CONH₂, —NHCONH₂, —CO—NHMe, —NHCONHMe, —CO—NMe₂or —NHCONMe₂; in particular H, methyl or methoxy. Preferably R^(4a) is Hor methyl. Very most preferably at least two of the substituentsselected from R^(4a), R^(4b), R⁵ are H.

[0759] R⁶⁰:

[0760] The substituents R⁶⁰ are preferably each defined as 1 to 4substituents independently selected from:

[0761] 1 to 3 substituents selected from halogen;

[0762] one of each substituent selected from: NO₂, cyano, azido; and

[0763] 1 to 3 substituents selected from:

[0764] a) (C₁₋₄) alkyl, (C₃₋₇)cycloalkyl, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl,(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, all of which optionally being substitutedwith R¹⁵⁰;

[0765] b) OR^(o);

[0766] e) N(R^(N2))R^(N1);

[0767] f) N(R^(N2))COR^(c);

[0768] j) COOR^(o);

[0769] k) CON(R^(N2))R^(N1);

[0770] I) phenyl, Het, (C₁₋₃alkyl)phenyl or (C₁₋₃alkyl)Het; wherein Hetis selected from furan, tetrahydrofuran, thiophene, tetrahydrothiophene,tetrahydropyran, pyridinyl, azetidine, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, homopiperidine andhomopiperazine;

[0771] wherein said R^(N1), R^(c) and/or R^(o) are optionallysubstituted with R¹⁵⁰ as defined.

[0772] R¹⁵⁰:

[0773] R¹⁵⁰ is preferably defined as 1 to 4 substituents independentlyselected from:

[0774] 1 to 3 fluorine-substituents;

[0775] one of each substituent selected from: chlorine, bromine, iodine,NO₂, cyano, azido; and

[0776] 1 to 3 substituents selected from:

[0777] a) (C₁₋₃) alkyl, CF₃, (C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all of which optionally substituted with R¹⁶⁰;

[0778] b) OR^(o);

[0779] ) N(R^(N2))R^(N1);

[0780] f) N(R^(N2))COR^(c);

[0781] j) COOR^(o);

[0782] k) CON(R^(N2))R^(N1);

[0783] wherein said R^(N1), R^(c) and/or R^(o) are optionallysubstituted with R¹⁶⁰ as defined.

[0784] R¹⁶⁰:

[0785] R¹⁶⁰ is preferably defined as 1, 2 or 3 substituentsindependently selected from:

[0786] 1, 2 or 3 fluorine substituents; and

[0787] one of each substituent selected from chlorine, bromine, iodine,CN, nitro, methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, COOH,COOCH₃, OH, OCH₃, OCF₃, NH₂, NHCH₃, N(CH₃)₂, SO₂NH₂, NHCOCH₃,SO₂NHCOCH₃, CONH₂, CONHCH₃ and CON(CH₃)₂.

[0788] R^(o)R^(c):

[0789] Preferably R^(o), R^(c) are independently selected from(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, phenyl,benzyl, Hot, (C₁₋₃)alkyl-Het; all of which are optionally substituted asdefined; and R^(o) may also be H.

[0790] R^(N1), R^(N2), R^(N3). R^(N4);

[0791] R^(N1) is preferably selected from H, (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, phenyl, benzyl,phenylethyl, Het, (C₁₋₃)alkyl-Het; wherein said alkyl, cycloalkyl,alkyl-cycloalkyl, phenyl, benzyl, phenylethyl, Het and alkyl-Het areoptionally substituted as defined; and

[0792] R^(N2), R^(N3), R^(N4) are independently selected from H, methyl,ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl; all of whichbeing optionally substituted with methyl, fluorine, carboxy ormethoxycarbonyl; and/or wherein said ethyl, n-propyl or i-propyl, butpreferably not the C-atom thereof directly bonded to the N-atom, isoptionally substituted with hydroxy, methoxy, amino, —NH(CH₃) and/or—N(CH₃)₂; and

[0793] in the case

[0794] a) of a group N(R^(N2))R^(N1), R^(N2) and R^(N1) or

[0795] b) of a group NR^(N3)—N(R^(N2))R^(N1), R^(N3) and R^(N1), orR^(N2) and R^(N1) may be covalently bonded together to form a 5-, 6- or7-membered saturated heterocycle which may have additionally oneheteroatom selected from O, N, and S, wherein said heterocycle isoptionally substituted as defined.

[0796] Included within the scope of this invention are all compounds offormula I as presented in Tables 1 to 8.

[0797] Preferred compounds according to this invention are listed in thetables. Particularly compounds of these tables are preferred which showan IC₅₀ value of below 200 nM, as for example those compounds includedin the claims 51, 52, 53, 54 and 55.

Polymerase Activity

[0798] The ability of the compounds of formula (I) to inhibit RNAsynthesis by the RNA dependent RNA polymerase of HCV can be demonstratedby any assay capable of measuring RNA dependent RNA polymerase activity.A suitable assay is described in the examples.

[0799] Specificity for RNA Dependent RNA Polymerase Activity

[0800] To demonstrate that the compounds of the invention act byspecific inhibition of HCV polymerase, the compounds may be tested forinhibitory activity in a DNA dependent RNA polymerase assay.

[0801] When a compound of formula (I), or one of its therapeuticallyacceptable salts, is employed as an antiviral agent, it is administeredorally, topically or systemically to mammals, e.g. humans, cattle, pigs,dogs, cats, rabbits or mice, in a vehicle comprising one or morepharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard biological practice.

[0802] For oral administration, the compound or a therapeuticallyacceptable salt thereof can be formulated in unit dosage forms such ascapsules or tablets each containing a predetermined amount of the activeingredient, ranging from about 25 to 500 mg, in a pharmaceuticallyacceptable carrier.

[0803] For topical administration, the compound can be formulated inpharmaceutically accepted vehicles containing 0.1 to 5 percent,preferably 0.5 to 5 percent, of the active agent. Such formulations canbe in the form of a solution, cream or lotion.

[0804] For parenteral administration, the compound of formula (I) isadministered by either intravenous, subcutaneous or intramuscularinjection, in compositions with pharmaceutically acceptable vehicles orcarriers. For administration by injection, it is preferred to use thecompounds in solution in a sterile aqueous vehicle which may alsocontain other solutes such as buffers or preservatives as well assufficient quantities of pharmaceutically acceptable salts or of glucoseto make the solution isotonic.

[0805] Suitable vehicles or carriers for the above noted formulationsare described in pharmaceutical texts, e.g. in “Remington's The Scienceand Practice of Pharmacy”, 19th ed., Mack Publishing Company, Easton,Penn., 1995, or in “Pharmaceutical Dosage Forms And Drugs DeliverySystems”, 6th ed., H. C. Ansel et al., Eds., Williams & Wilkins,Baltimore, Md., 1995.

[0806] The dosage of the compound will vary with the form ofadministration and the particular active agent chosen. Furthermore, itwill vary with the particular host under treatment. Generally, treatmentis initiated with small increments until the optimum effect under thecircumstance is reached. In general, the compound of formula I is mostdesirably administered at a concentration level that will generallyafford antivirally effective results without causing any harmful ordeleterious side effects.

[0807] For oral administration, the compound or a therapeuticallyacceptable salt is administered in the range of 10 to 200 mg perkilogram of body weight per day, with a preferred range of 25 to 150 mgper kilogram.

[0808] For systemic administration, the compound of formula (I) isadministered at a dosage of 10 mg to 150 mg per kilogram of body weightper day, although the aforementioned variations will occur. A dosagelevel that is in the range of from about 10 mg to 100 mg per kilogram ofbody weight per day is most desirably employed in order to achieveeffective results.

[0809] When the compositions of this invention comprise a combination ofa compound of formula I and one or more additional therapeutic orprophylactic agent, both the compound and the additional agent should bepresent at dosage levels of between about 10 to 100%, and morepreferably between about 10 and 80% of the dosage normally administeredin a monotherapy regimen.

[0810] When these compounds or their pharmaceutically acceptable saltsare formulated together with a pharmaceutically acceptable carrier, theresulting composition may be administered in vivo to mammals, such asman, to inhibit HCV polymerase or to treat or prevent HCV virusinfection. Such treatment may also be achieved using the compounds ofthis invention in combination with agents which include, but are notlimited to: immunomodulatory agents, such as α-, β-, or γ-interferons;other antiviral agents such as ribavirin, amantadine; other inhibitorsof HCV NS5B polymerase; inhibitors of other targets in the HCV lifecycle, which include but are not limited to, helicase, NS2/3 protease,NS3 protease, or internal ribosome entry site (IRES); or combinationsthereof. The additional agents may be combined with the compounds ofthis invention to create a single dosage form. Alternatively theseadditional agents may be separately administered to a mammal as part ofa multiple dosage form.

[0811] Methodology and Synthesis

[0812] Indole derivatives or analogs according to the present inventioncan be prepared from known monocyclic aromatic compounds by adaptingknown literature sequences such as those described by J. W. Ellingboe etal. (Tet. Lett. 1997, 38, 7963) and S. Cacchi et al. (Tet. Lett. 1992,33, 3915). Scheme 1, shown below wherein R¹, R², Sp, Y and L are asdescribed herein, illustrate how these procedures can be adapted to thesynthesis of compounds of formula I of this invention.

[0813] In carrying out the route illustrated in Scheme 1, a suitablyprotected form of 3-trifluoroacetamido-4-iodobenzoic acid I(i) isreacted with an alkyne I(ii) in the presence of a metal catalyst (e.g. apalladium metal complex such as PdCl₂(PPh₃)₂, Pd₂dba₃, Pd(PPh₃)₄ and thelike), a base (Et₃N, DIEA and the like or an inorganic basic saltincluding metal carbonates, fluorides and phosphates), and optionally inthe presence of an additional phosphine ligand (triaryl orheteroarylphosphine, dppe, dppf, dppp and the like). Suitable solventsfor this reaction include DMF, dioxane, THF, DME, toluene, MeCN, DMA andthe like at temperatures ranging from 20° C. to 170° C., oralternatively without solvent by heating the components together.Alternatively, the cross-coupling reaction can be carried out on asuitably protected form of 3-amino4-iodobenzoate and the amino group canbe trifluoroacetylated in the subsequent step as described by J. W.Ellingboe et al. (Tet. Lett. 1997, 38, 7963).

[0814] Reaction of the above diarylalkynes I(iii) with an enol triflateor equivalent under cross-coupling conditions similar to those describedabove gives after hydrogenation of the double bond, indole derivativesI(iv). Enol triflates are known and can be prepared from thecorresponding ketones by following known literature methods (forexample, cyclohexene triflate can be prepared from cyclohexanone,triflic anhydride and a hindered organic base such as2,6-di-tert-butyl4-methylpyridine). The hydrogenation of the double bondoriginally present in R³ can be carried out with hydrogen gas or ahydrogen donor (ammonium formate, formic acid and the like) in thepresence of a metal catalyst (preferably Pd) in a suitable solvent(lower alkyl alcohols, THF etc.).

[0815] The indole derivative I(iv) is then alkylated on nitrogen with anappropriate spacer (Sp) and further elaborated if necessary to giveN-alkylated indole carboxylates where Y, Sp and L are as defined herein.

[0816] Finally, following hydrolysis of the indole ester protectinggroup, the resulting carboxyindole derivative is converted to compoundsof formula 1 by coupling with the appropriate Z group. Condensation ofthe 6-indolecarboxylic acid with amines or alcohols can be accomplishedusing standard amide bond forming reagents such as TBTU, HATU, BOP,BroP, EDAC, DCC, isobutyl chloroformate and the like, or by activationof the carboxyl group by conversion to the corresponding acid chlorideprior to condensation with an amine. Any remaining protecting group isremoved following this step to give compounds of formula I.1.

[0817] Alternatively, compounds of formula I.1 can be prepared byelaboration from a pre-existing indole core by following adaptations ofliterature procedures as described, for example, by P. Gharagozloo etal. (Tetrahedron 1996, 52,10185) or K. Freter (J. Org. Chem. 1975, 40,2525). Such a methodology is illustrated in Scheme 2:

[0818] In carrying out the route illustrated in Scheme 2, commerciallyavailable 6-indolecarboxylic acid 2(i), which can also be preparedaccording to the method of S. Kamiya et al. (Chem. Pharm. Bull. 1995,43, 1692) is used as the starting material. The indole 2(i) is reactedwith a ketone 2(ii) under basic or acidic aldol-type conditions.Suitable conditions to affect this condensation include strong basessuch as alkali metal hydroxides, alkoxides and hydrides in solvents suchas lower alkyl alcohols (MeOH, EtOH, tertBuOH etc.), THF, dioxane, DMF,DMSO, DMA and the like at reaction temperature ranging from −20 ° C. to120° C. Alternatively, the condensation can be carried out under acidconditions using organic or mineral acids or both. Appropriateconditions include mixtures of AcOH and aqueous phosphoric acid attemperatures ranging from 15° C. to 120° C.

[0819] The carboxylic acid group is then protected in the form of anester (usually lower alkyl) using known methods. Halogenation (usuallybromination, but also iodination) of the 2-position of the indole 2(iii)gives 2(iv). Suitable halogenating agents include, for example,elemental bromine, N-bromosuccinimide, pyridine tribromide,dibromohydantoin and the corresponding iodo derivatives. Suitablesolvents for this reaction are inert to reactive halogenating agents andinclude for example hydrocarbons, chlorinated hydrocarbons (DCM, CCl₄,CHCl₃), ethers (THF, DME, dioxane), acetic acid, ethyl acetate, IPA, andmixtures of these solvents. Reaction temperature ranges from −40° C. to100° C. A method of choice to carry out the bromination of indoles asshown in Scheme 2 was described by L. Chu (Tet. Lett. 1997, 38, 3871).

[0820] The 2-bromoindole derivatives 2(iv) can be converted to fullysubstituted key intermediates I(v) by different sequences: (1)Trans-metallation of the 2-bromoindole to tin, boron, zinc species andthe like, followed by cross-coupling reaction with aryl or heteroarylhalides under transition metal catalysis as described in scheme 1 givesindole derivative 2(vii) which can then be elaborated on nitrogen asdescribed in scheme 1 to give key intermediate 1(v). In this approach,the indoleic NH is optionally protected with known protecting groupssuch as BOC, MOM, SEM, SO₂Ph and the like. The protecting group isremoved at a later stage of the sequence, prior to linker attachment.The conversion of 2-bromoindole derivatives 2(iv) to the correspondingorganotin species 2(vi) is carried out via initial low-temperature(usually −78° to −30° C.) halogen-metal exchange using an alkyllithiumreagent (e.g. nBuLi or tert-BuLi) or using lithium metal. The transient2-lithioindole species is then trapped with a trialkyltin halide (e.g.nBu₃SnCl or Me₃SnCl) or a borate ester (e.g. trimethyl or triisopropylborates). Alternatively, the lithioindole intermediate can be trappedwith zinc chloride to form the corresponding organozincate which canalso undergo transition metal-catalyzed cross-coupling with aromatic andheteroaromatic halides or triflates as described, for example, by M.Rowley (J. Med. Chem. 2001, 44,1603). Alternatively, species such as2(vi) where the indoleic NH is masked with a protecting group, can begenerated directly from 2(iii) by ester formation followed by indole NHprotection and abstraction of the 2-H proton with strong base (e.g.alkyllithiums, alkalimetal amides) followed by trans-metallation.Alternatively, 2-bromoindole 2(iv) can be cross-coupled directly to aryland heteroaryl stannanes or boronic acid derivatives to give 2(vii)directly. Boron or tin organometallic species are from commercialsources or can be prepared by standard literature procedures. (2) In asecond approach, 2-bromoindole 2(iv) is first elaborated on nitrogen togive 2(v) which is then cross-coupled to R² to give the sameintermediate 1(v) as described above.

[0821] Cross-coupling with organoboron reagents can be carried out byany variations of the Suzuki cross-coupling reaction reported in theliterature. This usually involves the use of a transition metal catalyst(usually Pd°), triaryl or triheteroarylphosphine ligands, an additivesuch as an inorganic chloride (e.g. LiCl), and a base (usually anaqueous inorganic base such as sodium or potassium carbonate orphosphate). The reaction is usually carried out in an alcoholic solvent(EtOH), DME, toluene, THF and the like at temperatures ranging from 25°C. to 140° C.

[0822] Cross-coupling with tin reagents can be carried out by anyvariations of the Stille cross-coupling reaction reported in theliterature. This usually involves the use of a transition metal catalyst(usually Pd°), triaryl or triheteroaryl phosphine ligands, and anadditive such as an inorganic chloride (e.g. LiCl) or iodide (e.g. Cul).Suitable solvents for this reaction include toluene, DMF, THF, DME andthe like at temperatures ranging from 25° C. to 140° C. IntermediateI(v) is then converted to compounds of formula I.1 as described forScheme 1.

[0823] Reaction conditions to alkylate the nitrogen of an indolederivative are well known to those skilled in the art and include theuse of strong bases such as alkali metal hydrides, hydroxides,carbonates, amides, alkoxides and alkylmetals, in the appropriatesolvent (such as THF, dioxane, DME, DMF, MeCN, DMSO, alcohols and thelike) at temperatures ranging from −78° C. to 140° C. An electrophilicform of Sp is used for the alkylation of the indole anion. Suchelectrophilic species include iodides, bromides, chlorides and sulfonateesters (mesylate, tosylate, brosylate or triflate).

EXAMPLES

[0824] The present invention is illustrated in further detail by thefollowing non-limiting examples. All reactions were performed in anitrogen or argon atmosphere. Temperatures are given in degrees Celsius.Flash chromatography was performed on silica gel. Solution percentagesor ratios express a volume to volume relationship, unless statedotherwise. Mass spectral analyses were recorded using electrospray massspectrometry. Hereinbefore and hereinafter the following abbreviationsor symbols are used:

[0825] AcOH: acetic acid

[0826] BOC or Boc: tedt-butyloxycarbonyl

[0827] BOP: benzotriazole-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate

[0828] BroP: Bromo tris(dimethylamino)phosphonium hexafluorophosphate

[0829] Bu: butyl

[0830] Cbz: carbobenzyloxy carbonyl;

[0831] DBA: dibenzylideneacetone;

[0832] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0833] DCC: 1,3-Dicyclohexyl carbodiimide

[0834] DCM: dichloromethane

[0835] DEPC: diethyl pyrocarbonate;

[0836] DIEA: diisopropylethylamine;

[0837] DMAP: 4-(dimethylamino)pyridine;

[0838] DME: dimethoxyethane;

[0839] DMF: N,N-dimethylformamide;

[0840] DMSO: dimethylsulfoxide;

[0841] dppe: 1,2-bis(diphenylphosphino)ethane

[0842] dppf: 1,1′-bis(diphenylphosphino)ferrocene

[0843] dppp: 1,2-bis(diphenylphosphino)propane

[0844] DTT: dithiothreitol

[0845] EDAC: see EDC

[0846] EDC: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride

[0847] EDTA: ethylenediaminetetraacetate

[0848] ES⁻: electro spray (negative ionization)

[0849] ES⁺: electro spray (positive ionization)

[0850] Et: ethyl;

[0851] Et₂O: diethyl ether;

[0852] EtOAc: ethyl acetate;

[0853] EtOH: ethanol

[0854] Fmoc: 9-Fluorenylmethyloxycarbonyl

[0855] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

[0856] HBTU: O-Benzotriazol-1-yl-N,N,N′,N′ tetramethyluroniumhexafluorophosphate

[0857] HOAT: 1-hydroxy-7-azabenzotriazole

[0858] HOBt: 1-Hydroxybenzotriazole

[0859] HPLC: high performance liquid chromatography;

[0860] IPA: isopropyl acetate

[0861]^(i)Pr: isopropyl

[0862]^(i)PrOH: isopropanol

[0863] Me: methyl;

[0864] MeCN: acetonitrile;

[0865] MeOH: Methanol;

[0866] MOM: methoxymethyl;

[0867] MS (ES): electrospray mass spectrometry;

[0868] NMP: N-methylpyrrolidone

[0869] PFU: plaque forming units;

[0870] Ph: phenyl;

[0871] RNAsin: A ribonuclease inhibitor marketed by Promega Corporation

[0872] RT: room temperature (approximatly 25° C.)

[0873] SEM: trimethylsilylethoxymethyl;

[0874] TBE: tris-borate-EDTA;

[0875] TBME: tert-butylmethyl ether

[0876] TBTU: 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate;

[0877] tBu: tert.-butyl;

[0878] TFA: trifluoroacetic acid;

[0879] TFAA: trifluoroacetic anhydride;

[0880] THF: tetrahydrofuran;

[0881] TLC: thin layer chromatography

[0882] Tris: 2-amino-2-hydroxymethyl-1,3-propanediol

[0883] UMP: uridine 5′-monophosphate

[0884] UTP: uridine 5′-triphosphate

Examples 1-33 Illustrate Methods of Synthesis of RepresentativeCompounds of this Invention Example 1

[0885]

Methyl 3-amino-4-iodobenzoate

[0886] 3-Amino-4-iodobenzoic acid (13.35 g, 50.8 mmol) was added to MeOH(150 mL) and SOCl₂ (4.8 mL, 65.8 mmol, 1.3 equivalent) was added. Themixture was refluxed for 3 h and then volatiles were removed underreduced pressure. The residue was co-evaporated 3×with Me OH and driedin vacuo (15.23 g).

Methyl 3-trifluoroacetamido-4-iodobenzoate

[0887] The aniline derivative from above (14.53 g, 52 mmol) wasdissolved in DCM (200 mL) and TFM (15 mL, 104 mmol) was added. The darkpurple solution was refluxed overnight. Volatiles were removed underreduced pressure and the residue was passed through a short pad ofsilica gel using DCM as eluent. The desired product was obtained as apink solid (13.81 g): MS (ES⁻) m/z 371.9 (M−H).

4-Phenylethynyl-3-(2,2,2-trifluoro-ethanoylamino)-benzoic acid methylester

[0888] The iodide from above (0.742 g, 2 mmol), phenylacetylene (0.37mL, 3.9 mmol, 1.7 equivalent) and Et₃N (6 mL) were charged in a dryflask under argon. PdCl₂(PPh₃)₂ (0.241 g, 0.3 mmol) was added and themixture was stirred at room temperature until judged complete by HPLCanalysis (˜5 h). The reaction mixture was concentrated to {fraction (1/2)} volume under reduced pressure and diluted with water (80 mL). Themixture was extracted with EtOAc (3×100 mL) and the organic extractwashed with 5% HCl (100 mL), after (100 mL) and brine (40 mL). Afterdrying over MgSO₄, the residue was purified by flash chromatographyusing 20% EtOAc-hexane as eluent to give the desired cross-coupledalkyne as a tan solid (0.442 g): MS (ES⁺) m/z 348.0 (MH⁺).

Methyl 3-(cyclohexenyl)-2-phenylindole 6-carboxylate

[0889] A flame-dried flask was charged with finely powdered anhydrousK₂CO₃ (0.153 g, 1.1 mmol) and the alkyne derivative from above (0.390 g,1.1 mmol). Dry DMF (4 mL) was added and the suspension degassed with astream of argon. The enol triflate derived from cyclohexanone, preparedfollowing the procedure described by A. G. Martinez, M. Hanack et al.(J. Heterocyclic Chem. 1988, 25, 1237) or equivalent methods describedin the literature (0.802 g, 3.3 mmol, 3 equivalents) was added followedby Pd(PPh₃)₄ (0.086 g, 0.07 mmol) and the mixture was stirred for 8 h atroom temperature. DMF was removed under vacuum and the residue purifiedby flash chromatography using DCM as eluent (0.260 g): MS (ES⁺) m/z332.2 (MH⁺).

Methyl 3-cyclohexyl-2-phenylindole-6-carboxylate

[0890] The material from above was hydrogenated (1 atm H₂ gas) over 20%Pd(OH)₂ in the usual manner, using MeOH as solvent. The desiredcyclohexane indole was isolated after filtration of the catalyst: MS(ES⁺) m/z 334.1 (MH⁺).

3-Cyclohexyl-2-phenylindole-6-carboxylic acid

[0891] The methyl ester from above (0.154 g, 0.15 mmol) was refluxedovernight in a mixture of MeOH (10 mL) and 2N NaOH (6 mL) until completehydrolysis had occurred as shown by HPLC analysis. After cooling to roomtemperature, 2N HCl (5 mL) was added followed by AcOH to pH 7. MeOH wasremoved under reduced pressure, water (50 mL) was added and the productextracted with EtOAc. The extract was washed with water and brine, anddried (MgSO₄). Removal of volatiles under reduced pressure gave thetitle indole carboxylic acid of example 1 as a light-orange solid (0.149g): MS (ES⁻) m/z 319 (M−H).

[0892] Following the same procedure but using 2-ethynylpyridine insteadof phenylacetylene, 3-cyclohexane-2-(2-pyridyl)indole-6-carboxylic acidwas obtained.

Example 2

[0893]

3-Cyclohexenyl-6-indole carboxylic acid

[0894] A 12 L round-bottomed flask was equipped with a reflux condenserand a mechanical stirrer, and the system was purged with nitrogen gas.6-indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) wascharged into the flask, followed by MeOH (5.5 L). After stirring for 10min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added.Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1equivalents) was added in portions over 10 min. The mixture was thenrefluxed for 48 h. After cooling to room temperature, water (4 L) wasadded and methanol removed under reduced pressure. The residual aqueousphase was acidified to pH 1 with concentrated HCl (˜1.2 L). Theresulting yellowish precipitate was collected by filtration, washed withwater and dried under vacuum at 50° C. The desired cyclohexenederivative was obtained as a beige solid (451.0 g, 100% yield).

3-Cyclohexyl-6-indole carboxylic acid

[0895] The unsaturated derivative from above was hydrogenated for 20 hunder 55 psi hydrogen gas pressure over 20% Pd(OH)₂/C (10.25 g) using1:1 THF-MeOH (2.5 L) as solvent. After filtration of the catalyst,volatiles were removed under reduced pressure and the residue wastriturated with hexane. The beige solid was collected by filtration,washed with hexane and dried under vacuum (356.4 g, 78% yield).

Methyl 3-cyclohexyl-6-indole carboxylate (thionyl chloride procedure)

[0896] A 5 L three-necked flask was equipped with a reflux condenser anda mechanical stirrer, and the system was purged with nitrogen gas. Theindole carboxylic acid from above (300.00 g, 1.233 mole) was chargedinto the flask and suspended in MeOH (2 L). Thionyl chloride ( 5 mL,0.0685 mole, 0.05 equivalent) was added dropwise and the mixture wasrefluxed for 48 h. Volatiles were removed under reduced pressure and theresidue was triturated with hexane to give a beige solid that was washedwith hexane and dried under vacuum (279.6 g, 88% yield).

Methyl 3-cyclohexyl-6-indole carboxylate (carbonate/iodomethaneProcedure)

[0897] A 2 L flask equipped with a dropping funnel and mechanicalstirrer was charged with crude 3-cyclohexyl-6-indole carboxylic acid(99.4 g, 0.409 mole) and anhydrous DMF (665 mL) was added followed byanhydrous potassium carbonate (78.13 g, 0.565 mole). Iodomethane (63.72g, 0.449 mole) was added dropwise over 35 min with stirring to theslurry which was then stirred overnight at room temperature untilcomplete disappearance of starting material (TLC). The resultingsuspension was then poured into water (1350 mL) and acidified to pH 4with 4N HCl (200 mL). The product was extracted into ether (3×1700 mL),washed with water and brine and dried (Na₂SO₄). Volatiles were removedunder reduced pressure and the residue was triturated with hexane (700mL). The beige solid was filtered and dried under vacuum (94.3 g, 90%yield).

Methyl 2-bromo-3-cyclohexyl-6-indole carboxylate

[0898] Adapting the procedure of L. Chu (Tet. Lett. 1997, 38, 3871)methyl 3-cyclohexyl-6-indole carboxylate (4.65 g, 18.07 mmol) wasdissolved in a mixture of THF (80 mL) and CHCl₃ (80 mL). The solutionwas cooled in an ice bath and pyridinium bromide perbromide (pyridinetribromide, 7.22 g, 22.6 mmol, 1.25 equivalent) was added. Afterstirring for 1.5 h at 0° C., the reaction was judged complete by TLC. Itwas diluted with CHCl₃ (200 mL), washed with 1M NaHSO₃ (2×50 mL),saturated aqueous NaHCO₃ (2×50 mL) and brine (50 mL). After drying overNa₂SO₄, the solvent was removed under reduced pressure and the residuecrystallized from TBME-hexane. The desired 2-bromoindole derivative wascollected by filtration, washed with hexane and dried (3.45 g).Evaporation of mother liquors gave a red solid that was purified byflash chromatography using 15% EtOAc in hexane yielding an additional3.62 g of pure material. Total yield was 5.17 g (85% yield).

Example 3

[0899]

3-Cyclopentenyl-6-indole carboxylic acid

[0900] A 3 L three-necked flask equipped with a mechanical stirrer wascharged with indole 6-carboxylic acid (220 g, 1.365 mole) and KOHpellets (764.45 g, 13.65 mole, 10 equivalents). Water (660 mL) and MeOH(660 mL) were added and the mixture heated to 75° C. Cyclopentanone(603.7 mL, 6.825 mole, 5 equivalents) was added dropwise over 18 h usinga pump. The reaction mixture was heated for an additional 3 h (afterwhich the reaction was judged complete by HPLC) and cooled to 0° C. for1 h. The precipitated potassium salt is collected by filtration, andwashed with TBME (2 ×500 mL) to remove cyclopentanone self-condensationproducts. The brown solid was re-dissolved in water (2.5 L) and thesolution washed with TBME (2×1 L). Following acidification to pH 3 withconc. HCl (425 mL), the beige precipitate was collected by filtration,washed with water (2×1 L) and dried under vacuum at 70° C. The crudeproduct weighed 275.9 g (88.9% mass recovery) and had an homogeneity of85% (HPLC).

3-Cyclopentyl-6-indole carboxylic acid

[0901] The crude product from above (159.56 g, 0.70 mole) was dissolvedin MeOH (750 mL) and 20% Pd(OH)₂ on charcoal (8.00 g) was added. Themixture was hydrogenated in a Parr apparatus under 50 psi hydrogen gasfor 18 h. After completion, the catalyst was removed by filtrationthrough celite and the solvent removed under reduced pressure. Theresulting brown solid was dried at 70° C. under vacuum for 12 h. Thecrude product (153.2 g) was obtained as a brown solid and was 77%homogeneous by HPLC.

Methyl 3-cyclopentyl-6-indole carboxylate

[0902] The indole carboxylic acid from above was converted to thecorresponding methyl ester using the carbonate/iodomethane proceduredescribed in example 2.

Methyl 2-bromo-3-cyclopentyl-6-indole carboxylate

[0903] The indole carboxylate from above was brominated using pyridiniumbromide perbromide following the procedure described in example 2.

Example 4 General Procedure for the Suzuki Cross-Coupling of aryl andheteroarylboronic acids with 2-bromoindole derivatives

[0904] Cross-coupling of aromatic/heteroaromatic boronic acid or esterderivatives with 2-bromoindoles such as the ones described in examples 2and 3 can be performed using any variations of the standardmetal-catalyzed Suzuki cross-coupling reaction as described in theliterature and well known to those skilled in the art. The followingexample serves to illustrate such a process and is non-limiting.

3-Cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylic acid methyl ester

[0905]

[0906] The 2-bromoindole of example 2 (8.92 g, 26.5 mmol),3-furanboronic acid (B. P. Roques et al. J. Heterocycl. Chem. 1975,12,195; 4.45 g, 39.79 mmol, 1.5 equivalent) and LiCl (2.25 g, 53 mmol, 2equivalents) were dissolved in a mixture of EtOH (100 mL) and toluene(100 mL). A 1M aqueous Na₂CO₃ solution (66 mL, 66 mmol) was added andthe mixture was degassed with argon for 45 min. Pd(PPh₃)₄ (3.06 g, 2.65mmol, 0.1 equivalent) was added and the mixture stirred overnight at75-85° C. under argon. Volatiles were removed under reduced pressure andthe residue re-dissolved in EtOAc (500 mL). The solution was washed withwater, saturated NaHCO₃ (100 mL) and brine (100 mL). After drying over amixture of MgSO₄ and decolorizing charcoal, the mixture was filtered andconcentrated under reduced pressure. The residual oil was trituratedwith a mixture of TBME (20 mL) and hexane (40 mL), cooled in ice and theprecipitated solid collected by filtration, washed with cold 25% TBME inhexane, and dried (3.09 g). The filtrate and washings from the abovetrituration were combined, concentrated and purified by flashchromatography using 10-25% EtOAc in hexane to give an additional 4.36 gof product. The total yield of the 2-(3-furyl)indole of example 4 was8.25 g.

Example 5

[0907] General Procedure for the Stille Cross-Coupling of aryl andheteroarylstannanes with 2-bromoindole derivatives

[0908] Cross-coupling of aromatic/heteroaromatic stannane derivativeswith 2-bromoindoles such as the ones described in examples 2 and 3 canbe performed using any variations of the standard metal-catalyzed Stillecross-coupling reaction as described in the literature and well known tothose skilled in the art. The following example serves to illustratesuch a process and is non-limiting.

[0909] A 1 L flask equipped with a reflux condenser was charged with2-trimethylstannylthiophene (11.16 g, 45 mmol), the 2-bromoindole ofexample 2 (7.00 g, 21 mmol) and anhydrous THF (300 mL). The solution wasdegassed by bubbling argon through the solution for 1 h. The catalyst,dichloro-bis(triphenylphosphine)palladium (1.76 g, 2.5 mmol) was addedand the mixture was stirred at 80° C. under an argon atmosphere for 24h. The reaction mixture was cooled to room temperature, filtered toremove solids and concentrated under reduced pressure. The residue waspurified by flash chromatography using 9:1 hexane-EtOAc as eluent, togive the desired 2-(2-thiophene)indole product of example 5 (7.10 g, 99%yield).

Example 6 General Procedure for N-alkylation of indole derivatives togive N-(methylcarboxy)indoles

[0910] The following example serves to illustrate such a process and isnon-limiting.

Methyl1-tert-butoxycarbonylmethyl-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylate

[0911] The indole derivative from example 4 (18.50 g, 57.4 mmol) wasdissolved in anhydrous DMF (120 mL) and the solution was cooled in anice bath under an argon atmosphere. NaH (60% oil dispersion, 2.88 g, 72mmol) was added in 3 portions and the mixture stirred 1 h at 0° C.tert-Butylbromoacetate (13.88 g, 71 mmol, 1.24 equiv.) was addeddropwise over 10 min and then the ice bath was removed. The reactionmixture was stirred overnight at room temperature. It was then dilutedwith TBME (1500 mL) and washed with 10% HCl (2×250 mL), water (3×500 mL)and brine (1×400 mL). After drying (Na₂SO₄), the solvent was removedunder reduced pressure to give a white solid. The solid was trituratedwith hexane (300 mL), filtered and triturated a second time with hexane(500 mL). Filtration followed by drying under vacuum gave the desiredtert-butyl ester as a white solid (21.6 g, 86% yield).

Methyl 1-carboxymethyl-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylate

[0912] The tert-butyl ester from above (21.5 g, 49 mmol) was dissolvedin dichloromethane (90 mL) and TFA (65.6 mL) was added dropwise to thesolution which was stirred for 5 h at room temperature. Volatiles wereremoved under reduced pressure, the residue was co-evaporated 3× withDCM and then dried under vacuum. The crude product was triturated with amixture of hexane (200 mL) and DCM (20 mL), filtered and dried undervacuum to give the title compound of example 6 as a white solid (18.62g, 99% yield).

Example 7

[0913]

[0914] The procedures for examples 4 and 6 were followed, using the2-bromoindole of example 3 as starting material.

Example 8

[0915]

[0916] The 2-bromoindole from example 2 was N-alkylated withtert-butylbromoacetate using NaH in DMF and the tert-butyl ester cleavedwith TFA as described in example 6 to give the title compound of example8 as a white solid.

Example 9 General Procedure for amidation of N-(methylcarboxy)indoleswith amines and saponification to give inhibitors of General Formula 1.1

[0917] The following example serves to illustrate such a process and isnon-limiting.

Methyl3-cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yi-2-oxo-ethyl)-1H-indole-6-carboxylate

[0918] The N-(methylcarboxy)indole derivative of example 6 (0.500 g,1.31 mmol, 1 equiv.), morpholine (141 μL, 1.6 mmol, 1.22 equiv.) andtriethylamine (432 μL, 3.1 mmol, 2.36 equiv.) were dissolved in amixture of THF (13 mL0 and DMF (3 m). TBTU (0.514 g, 1.6 mmol, 1.22equiv.) was added and the mixture stirred at room temperature for 3 h(complete by TLC). The reaction mixture was diluted with EtOAc andwashed successively with 10% aqueous HCl, water and brine. The extractwas dried (MgSO₄), concentrated and the residue purified by flashchromatography on silica gel using 70% EtOAc in hexane as eluent. Themethyl ester of example 9 was obtained as a yellow solid (0.498 g, 84%yield).

3-Cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indole-6-carboxylicacid

[0919] The methyl ester from above (0.480 g, 0.995 mmol) was dissolvedin a mixture of THF (8 mL) and MeOH (4 mL) and the solution heated to50° C. 4N NaOH (2.5 mL) was added dropwise to the mixture that was thenstirred for an additional 3.5 h at 50° C., at which it was judgedcomplete by TLC. The reaction mixture was evaporated to dryness underreduced pressure and the residue partitioned between 10% aqueous HCl andDCM. The organic phase was separated, dried (MgSO₄) and concentrated togive a residue that was purified by flash chromatography with 60% EtOAcin hexane+3% AcOH. The title compound of example 9 was obtained as ayellow solid (0.320 g, 74% yield).

Example 10

[0920]

Methyl2-bromo-3-cyclohexyl-1-dimethylcarbamoylmethyl-1H-indole-6-carboxylate

[0921] The 2-bromoindole derivative of example 8 (7.00 g, 17.75 mmol)was dissolved in THF (150 mL) and triethylamine (8.7 mL, 62.14 mmol, 3equiv.) was added followed by TBTU (7.13 g, 22.44 mmol, 1.25 equiv.).The white suspension was stirred for 20 min and dimethylaminehydrochloride (1.81 g, 22.2 mmol, 1.25 equiv.) was added followed by DMF(75 mL). After stirring overnight at room temperature, the reaction wasjudged complete by TLC (additional TBTU, Et₃N and dimethylaminehydrochloride can be added if required to complete the reaction). Thereaction mixture was diluted with EtOAc (200 mL), washed with 10% HCl(100 mL), water (12×320 mL) and brine. After drying over Na₂SO₄, thesolvent was removed under reduced pressure and the residue purified byflash chromatography to give the desired dimethyl amide as a white solid(6.10 g, 81% yield).

Methyl3-cyclohexyl-1-dimethylcarbamoylmethyl-2-(1-ethoxy-vinyl)-1H-indole-6-carboxylate

[0922] The 2-bromoindole derivative from above (6.10 g, 13.54 mmol) wascharged in a 100 mL flask equipped with a stirrer and reflux condenser.Anhydrous dioxane (50 mL) was added and tributyl(1-ethoxyvinyl)tin (6.27g, 17.37 mmol, 1.2 equiv.) was added. The reaction mixture was degassedby bubbling argon through the suspension for 40 min.Dichlorobis(triphenylphosphine)palladium (0.51 g, 0.72 mmol) was addedand the reaction mixture was stirred overnight at 100° C. under an argonatmosphere. The reaction mixture was then cooled to room temperature andvolatiles removed under reduced pressure. EtOAc (120 mL) was added andinsoluble solids removed by filtration through celite. Removal ofsolvent under reduced pressure and trituration of the residue with THFgave the desired product as a beige solid. Purification of the motherliquors by flash chromatography gave additional material. The totalyield was 5.36 g (89%).

Methyl2-(2-bromo-ethanoyl)-3-cyclohexyl-1-dimethylcarbamoylmethyl-1H-indole-6carboxylate

[0923] The vinyl ether from above (5.30 g, 12.85 mmol) was dissolved inTHF (300 mL) and the solution cooled in an ice-water bath. Water (30 mL)was added followed by N-bromosuccinimide (2.29 g, 12.85 mmol, 1 equiv.)in five equal portions over 10 min. After stirring for 1 h, additionN-bromosuccinimide (0.5 g) was added and after stirring for anadditional 30 min at 0° C., a final portion (0.5 g) was added tocomplete the reaction. The reaction mixture was diluted with ether (200mL) and water (100 mL) was added. The organic phase was separated andthe aqueous phase extracted with ether (2×100 mL). The extract waswashed with water (3×100 mL) and brine and then dried over Na₂SO₄.Removal of volatiles under reduced pressure gave a yellow oil that waspurified by flash chromatography on silica gel using 20-50% EtOAc inhexane as eluent to give the desired bromoketone of example 10 as ayellow solid (3.74 g, 62% yield).

Example 11

[0924]

[0925] The same procedures described in example 10 were used butdimethylamine hydrochloride was replaced with morpholine in step 1.

Example 12 General Procedure for the Conversion of bromemethylketones(such as those of Examples 10 and 11) to thiazolyl-substituted indolesand hydrolysis to give inhibitors of General Formula 1.1 where R2 is a(2-substituted 5-thiazolyl)heterocycle

[0926]

[0927] Bromomethylketones such as those described in examples 10 and 11were reacted with thioamides and thioureas and then saponified to givethe carboxylic acids of example 12. The following example serves toillustrate such a process and is non-limiting.

[0928] The bromomethylketone of example 11 (39.6 mg, 0.078 mmol, 1equiv.) was dissolved in DMSO (1 mL) and N-tertbutylthiourea (12.4 mg,0.094 mmol, 1.2 equiv.) was added. The mixture was stirred for 2 h atroom temperature. 10 N NaOH (24 μL) was added and after stirrihg for 4 hat room temperature, another portion of 10 N NaOH (24 μL) was added andthe mixture stirred 24 h at room temperature to complete the hydrolysis.The reaction mixture was then neutralized by addition of TFA and thetitle product of example 12 isolated directly from the reaction mixtureby preparative HPLC as a white amorphous TFA salt (21 mg).

Example 13

[0929]

[0930] The indole ester of example 4 (0.080 g, 0.247 mmol, 1 equiv.) wasdissolved in DMF (2 mL) and NaH (60% oil dispersion; 0.016 mg, 0.3 mmol,1.6 equiv.) was added. After stirring for 30 min, 1-bromopinacolone (45μL, 0.3 mmol, 22 equiv.) was added and the mixture stirred for 2.5 h atroom temperature. The reaction was quenched by addition of 10% aqueousHCl and extracted with TBME. The extract was washed with water, dried(MgSO₄) and concentrated to give a residue that was purified by flashchromatography on silica gel using 15-20% EtOAc in hexane as eluent. Themethyl ester of example 13 was obtained as a light-yellow solid. Themethyl ester from above (0.040 g, 0.095 mmol) was dissolved in a mixtureof THF (3 mL) and MeOH (2 mL) and 2.5 N NaOH (400 μL) was added. Themixture was stirred at 50° C. for 5 h after which the reaction wasjudged complete by TLC. Volatiles were removed under reduced pressureand the residue was partitioned between 10% aqueous HCl and DCM. Theorganic phase was washed with water, dried (Na₂SO₄) and concentrated.The residue was purified by preparative HPLC to give the title compoundof example 13 as a white amorphous solid (22 mg).

Example 14

[0931]

[0932] The amide of example 9 (0.060 g, 0.137 mmol, 1 equiv.) wasdissolved in THF (2 mL) and P₂S₅ (0.031 g, 0.07 mmol, 0.51 equiv.) wasadded. The mixture was stirred at 50° C. for 15 h after which anotherportion of P₂S₅ (0.020 g) was added. After stirring for an additional 2h at 50° C., the reaction mixture was concentrated under reducedpressure and the residue passed through a plug of silica gel using 60%EtOAc in hexane+3% AcOH as eluent. The fractions containing the productwere combined and after removal of solvents under reduced pressure, theresidue was purified by preparative HPLC to give the title compound ofexample 14 as a white amorphous solid (11 mg).

Example15

[0933] Procedures for the Preparation of benzimidazole-derivatives(Group Q¹ or Q²)

Example 15a(E)-3-[2-(1-Amino-cyclobutyl)-1-methyl-1H-benzoimidazol-5-yl]-acrylicacrylic acid methyl ester

[0934]

[0935] A mixture of 4-chloro-3-nitrocinnamic acid (500 mg, 2.2 mmol) andmethylamine (8 mL of 2M in THF, 16 mmol) were heated in a sealed tube at80° C. for 20 hours. The mixture was then cooled to room temperature andconcentrated to an orange solid that was used in the following stepwithout further purification.

[0936] The crude 4-methylamino-3-nitrocinnamic acid intermediate (488mg, 2.2 mmol) was dissolved in methanol (20 mL) and an ether solution ofdiazomethane was added until HPLC analysis indicated complete conversionof the acid to the methyl ester. The solution was concentrated todryness to obtain 540 mg of the methyl ester as an orange solid whichwas used further without purification.

[0937] The crude methyl ester (540 mg, ˜2.2 mmol) and SnCl₂ dihydrate(2.25 g, 10 mmol) were dissolved in ethanol (20 mL) and the mixture wasstirred at 80° C. for 4 hours. After that period, the mixture was cooledto room temperature and was slowly added to aqueous solution ofsaturated NaHCO₃. The reaction mixture was extracted with ethyl acetate(100 mL), the organic layer was dried over anhydrous MgSO₄ and thesolvent was removed under reduced pressure. The residue was purified byflash column chromatography, using a gradient of hexane in ethyl acetate(from 50% to 30%) to give the pure diamino cinnamate ester intermediateas a yellow solid (245 mg). ES⁺ MS m/z: 207.1 (M+H)⁺, ES⁻ MS m/z: 205.0(M−H)⁻

[0938] A sample of the above diamino intermediate (40 mg, 0.194 mmol)was suspended in CH₂Cl₂ (3 mL) and the aminocyclobutyl acid chlorideprepared from 1-aminocyclobutanecarboxylic acid, following a similarprocedure to that described in example 20, (31 mg, 0.18 mmol) was added.The reaction mixture was stirred at room temperature for 2 hours andthen concentrated to obtain a white solid. The solid was then dissolvedin acetic acid (5 mL) and heated to 60° C. for 20 hours. The reactioncrude was diluted with aqueous saturated NaHCO₃, extracted with CH₂Cl₂(2×50 mL) and brine, the organic layer was dried over anhydrous MgSO₄and the solvent was removed under reduced pressure to give the titlecompound of example 15a as a light brown foam (53 mg): ES⁺ MS m/z: 286.0(M+H)⁺

Example 15b(E)-3-[2-(1-Amino-cyclobutyl)-3-methyl-3H-benzoimidazol-5-yl]-acrylicacid methyl ester

[0939]

[0940] A mixture of 3-hydroxy-4-nitrobenzaldehyde (1.24 g, 7.4 mmol) and(carbethoxy-methylene)triphenylphophorane (2.6 g,7.4 mmol) weredissolved in THF (60 mL) and stirred at 60° C. for 2 hours. The mixturewas then concentrated and purified by flash column chromatography, usinghexane in ethyl acetate (70%) as the eluent, to obtain a thetrans-cinnamate ester derivative as a pure yellow solid (1.73 g).

[0941] The above cinnamate ester was dissolved in DMF (15 mL), methyliodide (1.35 mL, 21.7 mmol) and K₂CO₃ (3.0 g, 21.7 mmol) and the mixturewas stirred at room temperature for 20 hours. After that period, waterwas added and the precipitate formed was filtered and washed with water(2×). The solid was dissolved in ethyl acetate, dried over anhydrousMgSO₄, filtered and concentrated to dryness to give the crude methoxyanalogue as a white solid (˜1.7 g).

[0942] The crude 3-methoxy-4-nitrocinnamate ester (570 mg, 2.27 mmol)and methylamine (30 mL of 2M in THF, 60 mmol) were heated in sealed tubeat 85 ° C. for 40 hours. After that period the mixture was cooled toroom temperature, concentrated and purified by flash columnchromatography, using ethyl acetate in hexane (10%) as the eluent, toobtain the desired 3-methylamino-4-nitrocinnamate ester (˜160 mg). ES⁺MS m/z: 251.0 (M+H)⁺

[0943] Intermediate 3-methylamino-4-nitrocinnamate ester (˜150 mg) andSnCl₂ dihydrate (950 mg, 4.2 mmol) were dissolved in ethanol (10 mL) andthe mixture was stirred at 80° C. for 20 hours. The mixture was cooledto room temperature and concentrated to dryness. The residue wasdissolved in ethyl acetate (100 mL) and was slowly added to an aqueoussolution of saturated NaHCO₃ and stirred for 30 min. The organic layerwas then extracted with ice cold brine, dried over anhydrous MgSO₄ andthe solvent was removed under reduced pressure. The residue was purifiedby flash column chromatography (using a gradient from 70% to 60% ofhexane in ethyl acetate) to give the pure diamino cinnamate ester as ayellow solid (100 mg). ES⁺ MS m/z: 221.0 (M+H)⁺

[0944] The above diamino intermediate (100 mg, 0.45 mmol) was suspendedin CH₂Cl₂ (5 mL) and the aminocyclobutyl acid chloride prepared from1-aminocyclobutanecarboxylic acid, following a similar procedure to thatdescribed in example 20 (77 mg, 0.45 mmol) was added. The reactionmixture was stirred at room temperature for 2 hours and thenconcentrated to obtain a white solid. The solid was then dissolved inacetic acid (5 mL) and heated to 60° C. for 16 hours. The reactionmixture was cooled and the precipitate formed was filtered and washedwith cold acetic acid, and then dissolved in ethyl acetate (100 mL) andwashed with aqueous saturated NaHCO₃ (2×) and ice cold brine. Theorganic layer was dried over anhydrous MgSO₄ and the solvent was removedunder reduced pressure to give the title compound of example 15b(E)-3-[2-(1-amino-cyclobutyl)-3-methyl-3H-benzoimidazol-5-yl]-acrylicacid methyl ester as a white solid (58 mg).

[0945] Note: it will be apparent to the person skilled in the art thatthe (carbethoxymethylene)triphenylphosphorane used in this procedure canbe replaced by appropriately substituted derivatives to prepareanalogues bearing various substituents on the cinnamate double bond. Inaddition, cinnamate methyl esters can also be prepared in an analogousfashion using the appropriate reagent.

Example 15c 2-(1-Amino-cyclobutyl)-1H-benzoimidazole-5-carboxylic acidmethyl ester

[0946]

[0947] Methyl 3,4-diaminobenzoate (320 mg, 1.9 mmol), the SEM-protectedcyclobutylamino acid (500 mg, 1.9 mmol) of example 21 and TBTU (836 mg,2.2 mmol) were dissolved in CH₂Cl₂ (10 mL) and DIPEA (1.1 mL, 6 mmol)was added. The reaction mixture was stirred at room temperature for 20hours, then diluted with ethyl acetate (100 mL) and extracted withaqueous saturated NaHCO₃ (2×) and brine. The organic layer was driedover anhydrous MgSO₄ and filtered, and the solvent was evaporated undervacuum to isolate the crude amide intermediate as a yellow oil (407 mg).The amide was dissolved in acetic acid (10 mL) and stirred at 70 ° C.for 3 hours to induce dehydration and cyclization to the benzymidazole.The reaction mixture was concentrated to dryness, diluted with ethylacetate (100 mL) and washed with 10% aqueous citric acid (2×), aqueoussaturated NaHCO₃ and brine. The organic layer was dried over MgSO₄,filtered and concentrated to dryness. The residue was purified by flashcolumn chromatography, using a solvent gradient of hexane in ethylacetate (from 80% to 50%), to give the SEM-protected benzymidazoleintermediate as a pink solid (574 mg). ES⁺ MS m/z: 390.2 (M+H)⁺Theprotecting group was then removed by dissolving this solid in TFA/CH₂Cl₂(2 mL, 1:1 ratio) and stirring the solution at room temperature for 2hours. The solution was evaporated to dryness under vacuum to give theproducts, 2-(1-amino-cyclobutyl)-1H-benzoimidazole-5-carboxylic acidmethyl ester, which was used for the synthesis of inhibitors withoutfurther purification.

Example 16

[0948]

[0949] wherein R, R′, R″ are H or alkyl. The following example serves toillustrate such as process and is non-limiting:

1-Allyl-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylic acid

[0950] The indole derivative of example 4 (0.050 g, 0.156 mmol, 1equiv.) was dissolved in DMF (1 mL) and the solution was cooled inice-water. NaH (60% oil dispersion, 7 mg, 0.175 mmol, 1.13 equiv.) wasadded and the ice-bath removed. Allyl bromide (15 μL, 0.17 mmol, 1.11equiv.) was added and the reaction stirred overnight at room temperature(complete by TLC). The reaction mixture was diluted with DMSO (1 mL) and5N NaOH (200 μL) was added. The mixture was stirred at 60° C. for 3 h(complete by HPLC), neutralized by addition of TFA and the productisolated directly from the reaction mixture by preparative HPLC. Thetitle product of example 16 was isolated as a white amorphous solid (33mg).

Example 17

[0951]

Methyl1-(2-tert-butoxycarbonyl-ethyl)-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylate

[0952] The indole ester of example 4 (0.100 g, 0.31 mmol, 1 equiv.) wasdissolved in DMF (2 mL) and NaH (60% oil dispersion, 0.020 g, 0.50 mmol,1.6 equiv.) was added. After stirring for 1 h at room temperature,tert-butyl 3-bromopropionate (0.102 g, 0.49 mmol, 1.6 equiv.) was addedand the mixture stirred overnight at room temperature. The solvent wasthe removed under vacuum and the residue purified by flashchromatography on silica gel to give the N-alkylated indole (41 mg).

Methyl1-(2-carboxy-ethyl)-3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylate

[0953] The tert-butyl ester from above (40 mg) was dissolved in DCM (1mL) and TFA (2 mL) was added. The mixture was stirred for 1 h at roomtemperature after which volatiles were removed under reduced pressure.The residue was co-evaporated twice with DCM and used as such in thenext step.

3-Cyclohexyl-2-furan-3-yl-1-(3-morpholin-4-yl-3-oxo-propyl)-1H-indole-6-carboxylicacid

[0954] The acid from above (18 mg, 0.046 mmol, 1 equiv.) was dissolvedin DMSO (0.5 mL) and HATU (26 mg, 0.069 mmol, 1.5 equiv.), DIEA (16 pL,0.092 mmol, 2 equiv.) and morpholine (8 μL, 0.092 mmol, 2 equiv.) wereadded. The mixture was stirred for 3.5 h at room temperature (completeby HPLC). 5N NaOH (184,μL) was added and the mixture stirred overnightat room temperature. The reaction was then quenched by addition of AcOH(100 μL) and the product isolated directly by preparative HPLC. Thetitle compound of example 17 was isolated as a brownish amorphous solid(1.2 mg).

Example 18

[0955]

[0956] The acid derivative of example 6 (0.050 g, 0.13 mmol, 1 equiv.)was dissolved in DCM (5 mL) and EDCl (25 mg, 0.13 mmol, 1 equiv.), DMAP(16 mg, 0.13 mmol, 1 equiv.) and benzene sulfonamide (23.6 mg, 0.15mmol, 1.14 equiv.) were added. The greenish reaction mixture was stirredfor 24 h at room temperature (>80% conversion by HPLC). The reactionmixture was diluted with DCM, washed with 10% aqueous HCl and dried(Na₂SO₄). Evaporation of the solvent gave a residue that was dissolvedin DMSO (2 mL) and 2.5N NaOH (0.5 mL) was added. The mixture was stirredfor 2.5 h at room temperature (complete by HPLC), neutralized with AcOHand the product isolated directly by preparative HPLC. The titlecompound of example 18 was obtained as a beige amorphous solid (15 mg).

Example 19(E)-3-(4-{[1-(5-Amino-1,3-dioxinan-5-yl)-methanoyl]-amino}-phenyl)-acrylicacid ethyl ester (Building Block for Group L and/or Z According toFormula I)

[0957]

1,3-Dioxinane-5,5-dicarboxylic acid diethyl ester

[0958] A 500 mL round-bottomed flask equipped with a reflux condenserwas charged with diethyl bis(hydroxymethyl)malonate (5.00 g, 22.7 mmol,1.00 equiv.), 1,3,5-trioxane (4.09 g, 45.41 mmol, 2.00 equiv.),(1R)-(−)-10-camphorsulfonic acid (CSA) (10.55 g, 45.41 mmol, 2.00equiv.), and 4Åmolecular sieves (2.00 g). Chloroform (200 mL) was thenadded and the mixture was refluxed for 72 h (complete by TLC). Thereaction mixture was filtered on celite and the filtrate was washed withaqueous 0.5 N sodium hydroxide (100 mL). The layers were separated andthe aqueous phase was back-extracted with chloroform (50 mL). Organiclayers were then combined, dried (MgSO₄), filtered and concentrated invacuo. The resulting crude mixture was finally purified by flashchromatography (eluting hexane/EtOAc 4:1) to give the desired dioxanemalonate as a colorless oil (3.41 g, 65%).

1,3-Dioxinane-5,5-dicarboxylic acid ethyl ester

[0959] A 50 mL round-bottomed flask was charged with the intermediatefrom above (1.00 g, 4.31 mmol, 1.00 equiv.). EtOH and aqueous 1.0 Nsodium hydroxide (4.50 mL, 4.50 mmol, 1.05 equiv.) was added and theresulting mixture was stirred at RT for 16 hrs (TLC monitoring). Thenthe pH of the reaction mixture was brought to 12 using aqueous 1.0 Nsodium hydroxide and EtOH was removed in vacuo. The resulting aqueoussolution was diluted with water (50 mL) and extracted with EtOAc (2×50mL). Then the pH of the aqueous solution was brought to 2 using aqueousconc. HCl. The aqueous solution was extracted with EtOAc (2×50 mL).Organic phases were combined, dried (MgSO₄), filtered and concentratedin vacuo. To give the desired monoester contaminated with ˜10 mole % ofthe corresponding diacid as a colorless oil (0.91 g). The material wasused in the next step without further purification.

5-(2-Trimethylsilanyl-ethoxycarbonylamino)-1,3-dioxinane-5-carboxylicacid ethyl ester

[0960] In a 100 mL round-bottomed flask equipped with a reflux condenserwas mixed the above monoester (0.91 g, 4.31 mmol of monoacid, 1.00equiv.) contaminated with approximately 10% of diacid, anhydrous toluene(20 mL) and triethylamine (TEA) (750 μL, 5.39 mmol, 1.25 equiv.) undernitrogen. The resulting mixture was heated to 80° C. and thendiphenylphosphoryl azide (1.07 mL, 4.96 mmol, 1.15 equiv.) was slowlyadded in one minute. The mixture was then stirred at 80° C. for 1 h.2-(Trimethylsilyl)ethanol (680 μL, 4.74 mmol, 1.10 equiv.) was addeddrop wise and the reaction mixture was stirred at 110° C. After 24 h,the reaction was judged to be complete. The reaction mixture was thendiluted with EtOAc (50 mL) and washed successively with water (25 mL),aqueous 1.0 N HCl and sat. aqueous sodium carbonate. The organic layerwas then dried (MgSO₄), filtered and concentrated in vacuo. The crudematerial was finally purified by flash chromatography (elutingHexane/EtOAc 9:1) to give the desired SEM-carbamate-protected aminoester as a colorless oil (0.61 g, 45%).

5-(2-Trimethylsilanyl-ethoxycarbonylamino)-1,3-dioxinane-5-carboxylicacid

[0961] The ester from above (612 mg, 1.91 mmol, 1.00 equiv.) wasdissolved in 15 mL of a 4:1 THF/MeOH mixture in a 50 mL round-bottomedflask. Aqueous. 10 N Sodium hydroxide (0.96 mL, 9.56 mmol, 5.00 equiv.)was then added, and the mixture was stirred at RT for 4 h (TLCmonitoring). The solvent was removed in vacuo and the residue wasdissolved in dichloromethane (20 mL). The organic phase was washed with20 mL of 1.0 N aqueous HCl, layers were separated and the organic phasewas back-extracted with dichloromethane (2×20 mL). Organic layers werecombined, dried (MgSO₄), filtered and concentrated in vacuo to give thedesired acid as a white foam (466 mg, 84%).

(E)-3-[4-({1-[5-(2-Trimethylsilanyl-ethoxycarbonylamino)-1,3-dioxinan-5-yl]-methanoyl}-amino)-phenyl]-acrylicacid ethyl ester

[0962]5-(2-trimethylsilanylethoxycarbonylamino)-1,3-dioxane-5-carboxylic acidfrom above (0.050 g, 0.17 mmol), ethyl-4-aminocinnamate (0.036 g, 0.19mmol), HATU (0.098 g, 0.26 mmol), HOAt (0.035 g, 0.26 mmol) and2,4,6-collidine (0.062 mL, 0.51 mmol) were combined in anhydrous DMSO (1mL). The solution was warmed to 60° C. and stirred for 6 h beforeanother 1.5 equivalents of HATU was added and stirring was continued foranother 2 hours to ensure complete consumption of the acid. The reactionmixture was diluted with dichloromethane and washed with 1N HCl (×2).The organic phase was dried with MgSO₄, filtered and concentrated. Theresidue was subjected to flash chromatography to afford 0.043 g (54%) ofthe protected amide derivative as a yellow oil.

(E)-3-(4-{[1-(5-Amino-1,3-dioxinan-5-yl)-methanoyl]-amino}-phenyl)-acrylicacid ethyl ester

[0963] Deprotection of the SEM carbamate from above was carried out withTFA-DCM in the usual manner.

Example 20 General Procedure for Coupling α,α-disubstituted amino acidsto aromatic amines Ethyl(E)-3-[4-(2-amino-2-methyl-propanoylamino)-phenyl]-acrylate

[0964]

[0965] Adapting the procedure described by E. S. Uffelman et al. (Org.Lett. 1999, 1, 1157), 2-aminoisobutyric acid was converted to thecorresponding amino acid chloride hydrochloride: 2-oxazolidinone (12.30g, 0.141 mole) was dissolved in MeCN (150 mL) and phosphorouspentachloride (49.02 g, 0.235 mole, 1.7 equivalent) was added in oneportion. The homogeneous mixture was stirred for 24 h at roomtemperature. 2-Aminoisobutyric acid (14.55 g, 0.141 mole) was added andthe suspension was stirred for 48 h at room temperature. The desiredacid chloride hydrochloride was collected by filtration, washed withMeCN and dried under vacuum. Other α, α-disubstituted amino acidchloride hydrochlorides can be prepared in an analogous fashion startingfrom the corresponding amino acid (e.g. 1-aminocyclobutanecarboxylicacid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylicacid and the like).

[0966] The acid chloride (12.778 g, 80 mmol, 1.4 equivalent) wassuspended in DCM (200 mL) and ethyl 4-aminocinnamate (11.045 g, 57.7mmol, 1 equivalent) was added. Pyridine (7.01 mL, 86.6 mmol, 1.5equivalent) was added drop wise and the mixture was stirred for 3.5 h atroom temperature. The reaction was then poured into a mixture of 1N NaOH(25 mL) and saturated aqueous NaHCO₃ (100 mL) and extracted with EtOAc.The organic phase was washed with aqueous NaHCO₃, water and brine, anddried over MgSO₄. Removal of solvent under reduced pressure gave thetitle compound as a white solid (15.96 g, 101% yield).

Example 21

[0967]

[0968] Diethyl 1,1-cyclobutanedicarboxylate (20.00 g, 100 mmol) and KOH(6.60 g, 100 mmol) were refluxed in EtOH (100 mL) for 2 h. After coolingto room temperature, volatiles were removed under reduced pressure andthe residue partitioned between Et₂O and 4N HCl. The organic extract waswashed with water and brine, and dried over MgSO₄. Removal of thesolvent under reduced pressure gave the monoester as a clear oil (14.45g, 84% yield).

[0969] The monoester from above (14.45 g, 84 mmol), Et₃N (14.1 mL, 100mmol) and diphenylphosphoryl azide (DPPA) (24.05 g, 87.4 mmol) weredissolved in dry toluene (114 mL) and the mixture heated at 80° C. for 1h and 110° C. for an additional hour. Trimethylsilylethanol (9.94 g, 100mmol) was added in one portion and the mixture refluxed for 48 h.Toluene was then removed under reduced pressure and the residuedissolved in DCM. The solution was washed with water and brine and driedover MgSO₄. Concentration under reduced pressure gave a dark oil whichwas purified by passage through a pad of silica gel using 30% EtOAc inhexane as eluent. The desired carbamate was obtained as a clear yellowliquid (21.0 g). The carbamate from above (1.50 g, 5.22 mmol) wasdissolved in THF (5 mL) and 2N NaOH (5 mL) was added. The mixture wasstirred at 70° C. for 1 h. Following dilution with water, the aqueousphase was washed with Et₂O to remove unreacted starting material. Theaqueous phase was then acidified with KHSO₄ and the product extractedwith EtOAc. The desired free carboxylic acid was obtained as an oil(1.25 g).

[0970] The acid from above (0.519 g, 2.0 mmol) was dissolved in DCM (10mL). DIEA (1.39 mL, 8.0 mmol, 4 equivalents) was added, followed byethyl 4-aminocinnamate (0.573 g, 3.0 mmol, 1.5 equivalent) and HATU(1.143 g, 3.0 mmol, 1.5 equivalents). The mixture was stirred at roomtemperature for 3 days. The reaction was poured into TBME (100 mL) andthe solution washed successively with 10% aqueous citric acid (2×25 mL)and saturated aqueous NaHCO₃ (25 mL), and dried over MgSO₄. The solventwas removed under reduced pressure and the residue stirred with TFA (10mL) for 30 min. Volatiles were then removed under reduced pressure andthe residue was co-evaporated twice with hexane. The crude product wasdissolved in TBME (60 mL) and the solution washed with 1N NaOH (2×25mL). After drying (Na₂SO₄), volatiles were removed in vacuum to give thetitle compound as a beige solid (0.500 g).

Example 22

[0971]

[0972] Diazomethane was slowly added to a solution of4-chloro-3-nitrocinnamic acid in CH₃OH/CH₂Cl₂ until the yellow colorpersisted, indicating the presence of excess diazomethane. The solutionwas evaporated to dryness under reduced pressure and the residue wasdissolved in DMSO. The solution was heated to 140° C. and ammonia gaswas bubbled through for a period of 4 hours. The mixture was cooled toroom temperature and degassed with N₂, and poured onto ice. Theprecipitate formed was filtered, washed with cold water and dried undervacuum for 16 hours to give the crude 4-amino-3-nitrocinnamic ester as ayellow solid (2.05 g). The solid was dissolved in ethanol (40 mL),SnCl₂.dihydrate (9.91 g, 43.9 mmol) was added and the reaction mixturewas heated to reflux for 4 hours. The solution was concentrated toremove most of the ethanol, diluted with EtOAc and saturated aqueousNaHCO₃ was added slowly. The mixture was stirred for 20 min, the organiclayer was extracted with brine, dried over anhydrous Na₂SO₄ andevaporated to dryness under reduced pressure. The residue was purifiedby flash column chromatography (using 50% to 70% EtOAc in hexane) togive the diamino intermediate as a yellow solid (1.03 g).

[0973] A portion of the 3,4-diaminocinnamate ester (186 mg, 0.970 mmol)and N-Boc-1-aminocyclopentane-1-carboxylic acid (222 mg, 0.970 mmol)were coupled in the presence of HATU/DIEA (in the usual way) and theamide product formed was dehydrated by heating at 65° C. in a solutionof acetic acid (4 mL). The reaction residue was purified by reversedHPLC to give the N-Boc protected(Z)-3-[2-(1-amino-cyclopentyl)-1H-benzoimidazol-5-yl]-acrylic acid ethylester.

[0974] The Boc protecting group was removed with 4N HCl in dioxane inthe usual way to give(Z)-3-[2-(1-amino-cyclopentyl)-1H-benzoimidazol-5-yl]-acrylic acid ethylester as yellow foam (200 mg).

Example 23

[0975]

[0976] N-Fmoc-(3-N-Boc)-(S)-cucurbitine (0.495 g, 1.09 mmol), ethyl4-aminocinnamate (0.300 g, 1.57 mmol), HOAt (0.224,1.65 mmol) and HATU(0.626 g, 1.65 mmol) were dissolved in DMF (7 mL). To this mixture,2,4,6-collidine (0.435 mL, 3.30 mmol) was added and the solution wasstirred at room temperature for 2 days. The reaction mixture was pouredinto EtOAc (100 mL) and the solution washed successively with 10%aqueous citric acid (2×25 mL), saturated aqueous NaHCO₃ (25 mL) andbrine (25 mL), and dried over anhydrous MgSO₄. The solvent was removedunder reduced pressure and the residue was dissolved in CH₂Cl₂, DBU(0.658 mL, 4.4 mmol) was added and the reaction mixture was stirred atroom temperature for 15 hours.

[0977] The reaction mixture was poured into EtOAc (100 mL) and thesolution washed successively with saturated aqueous NaHCO₃ (2×25 mL) andbrine (25 mL), and dried over anhydrous MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by flash columnchromatography (40% to 70% EtOAc in hexane) to give the product shownabove as a white solid (0.234 mg).

Example 24

[0978]

[0979] Commercially availableN-Fmoc-amino-(3-N-Boc-piperidinyl)carboxylic acid was coupled to theethyl ester of 4-aminocinnamic acid using HATU/HOAT/collidine in DMF andthe Fmoc protecting group was removed with piperidine to give the titlecompound of example 24 in racemic form.

[0980] Racemic N-Fmoc-amino-(3-N-Boc-piperidinyl)carboxylic acid, couldalso be resolved into its two enantiomers by preparative HPLC on achiral support (Chiralcel OD, 10 micron, 2.00 cm I.D.×25 cm), using 35%H₂O in MeCN as the eluent. Enantiomeric amines could then be coupled toindole carboxylic acids to prepare enantiomerically pure inhibitors.

Example 25

[0981]

[0982] 4′-Nitro-2-bromoacetophenone (6.100 g, 25 mmol) and ethylthioxamate (3.460 g, 26 mmol) were dissolved in MeOH (20 mL) and thesolution was refluxed for 1 h. After cooling to room temperature, theprecipitated solid was collected by filtration, washed with cold MeOHand dried under vacuum (5.15 g, 75% yield).

[0983] A suspension of the nitroester from above (2.50 g, 8.98 mmol) and20% Pd(OH)₂ on carbon (200 mg) in 2:1 EtOH-THF (60 mL) was stirred for 3h under 1 atm of hydrogen gas. The suspension was filtered to remove thecatalyst and volatiles removed under reduced pressure to give the titlecompound of example 25 as a reddish foam (2.05 g, 92% yield).

Example 26

[0984]

[0985] para-Bromoaniline (13.0 g, 76 mmol) and Boc₂O (19.8 g, 91 mmol)were dissolved in toluene (380 mL) and stirred at 70° C. for 15 h. Thereaction mixture was cooled to RT, evaporated to dryness, re-dissolvedin EtOAc and washed with 0.1M HCl and brine. The organic solution wasdried over anhydrous MgSO₄, evaporated to dryness and purified by flashcolumn chromatography, using 5% to 10% EtOAc in hexane as the eluent, toobtain the Boc-protected aniline (23 g). The Boc-protected bromoaniline(10.7 g, 39.2 mmol) was dissolved in anhydrous THF (75 mL) in a flaskequipped with an overhead stirrer. The solution was cooled to 0° C. andMeLi (1.2 M in Et₂O, 33 mL, 39.2 mmol) was added drop wise whilemaintaining the internal temperature below 7° C. The reaction mixturewas stirred at 0° C. for 15 min and then cooled to −78° C. before n-BuLi(2.4 M in hexane, 17 mL, 39.2 mmol) was added drop wise, maintaining theinternal temperature below −70 C.). The reaction mixture was stirred at−78° C. for 1 h, B(OEt)₃ (17 mL, 98 mmol) was added drop wise (internaltemperature <−65° C.) and stirring was continued for 45 min at −78° C.and at 0° C. for 1 h. The reaction mixture was then treated with 5%aqueous HCl (˜100 mL, to pH ˜1) for 15 min and NaCl(s) was added tosaturate the aqueous layer. The aqueous layer was extracted with 0.5 MNaOH (4×100 mL) and the combined aqueous layers were acidified with 5%HCl (150 mL, to pH ˜1) and extracted with Et₂O (3×200 mL). The combinedorganic layers were dried over anhydrous MgSO₄, filtered andconcentrated to give the N-Boc carbamate of 4-aminophenylboronic acid asa solid (7.5 g).

[0986] Thiourea (7.60 g, 100 mmol) and ethyl bromopyruvate (12.6 mL, 100mmol) were mixed and heated to 100° C. for 45 min. After cooling of thereaction mixture, the solid obtained was triturated with acetone,filtered and recrystallized from EtOH to obtain the desiredaminothiazole product (10.6 g, 40 mmol). The aminothiazole was thenadded slowly (over a period of 20 min) to a solution of t-butyinitrite(6.2 g, 60 mmol) and CuBr₂ (10.7 g, 48 mmol) in MeCN (160 mL) at 0° C.The reaction mixture was allowed to warm-up to RT and to stirred for 2.5h. The mixture was then added to an aqueous HCl solution (20%) andextracted with Et₂O (2×400 mL). The organic layer was washed withaqueous HCl (10%), dried over anhydrous MgSO₄ and evaporated to dryness.The desired bromothiazole product was isolated in ˜85% yield (4.3 g)after flash column chromatography using 15% EtOAc in hexane as theeluent.

[0987] To a de-gassed solution of the bromothiazole product (230 mg,0.97 mmol), the boronic acid derivative from above (230 mg, 0.97 mmol)and aqueous Na₂CO₃ (2M, 3 mL) in DME (3 mL), a catalytic amount ofPd(PPh₃)₄ (56 mg, 0.049 mmol) was added and the reaction mixture wasstirred at 80° C. under argon for 20 h. The reaction mixture was thencooled to RT, diluted with EtOAc and extracted with brine, aqueousNaHCO₃ (2×) and brine. The organic layer was dried over anhydrous MgSO₄and concentrated to dryness. The carbamate-ester product was isolatedafter flash column chromatography using 20% to 30% EtOAc in hexane: 180mg. The aniline hydrochloride of example 26 was isolated after removalof the Boc protecting group with 4N HCl in dioxane for 30 min.

Example 27 Ethyl 5-amino-1-methyl-1H-indole-2-carboxylate

[0988]

[0989] The ethyl ester of 5-nitroindole-2-carboxylic acid (0.300 g, 1.28mmol) was dissolved in anhydrous DMF (6 mL) and NaH (0.078 g, 60%,1.92mmol) was added. The reaction was stirred at RT for 20 min, then Mel(160 μL, 2.56 mmol) was added and stirring was continued for 3 h. Thereaction was quenched with the addition of aqueous NaHCO₃ (˜1%) whilestirring vigorously. The brown solid formed (0.096 g) was filtered anddried in air overnight.

[0990] The N-methyl nitro derivative (196 mg, 0.79 mmol) was thendissolved in DMF (4 mL), H₂O (400 μL) and SnCl₂.2H₂O (888 mg, 3.95 mmol)were added, and the mixture was stirred at 60° C. for 3 h. The mixturewas then partitioned between 10% aqueous NaHCO₃ and EtOAc and stirredvigorously. The aqueous layer was re-extracted with EtOAc and thecombined EtOAc layers were washed with brine, dried over anhydrous MgSO₄and concentrated to dryness. The residue was purified by flash columnchromatography, using 1:1 ration EtOAc/hexane as the eluent, to obtainthe pure 5-aminoindole derivative (118 mg) of example 27.

Example 28 Ethyl5-{[1-(4-amino-1-ethyl-piperidin-4-yl)-methanoyl]-amino}-1-methyl-1H-indole-2carboxylate

[0991]

[0992] The 5-aminoindole derivative of example 27 was coupled toN-Fmoc-amino-(4-N-Boc-piperidinyl)carboxylic acid. The Boc protectinggroup was removed with 25% TFA in CH₂Cl₂ in the usual way, and theproduct was then dissolved in EtOH (6 mL). AcOH (133 mg), acetaldehyde(33 mg, 0.74 mmol) and NaCNBH₃ (23mg, 0.37 mmol) were added and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was concentrated to remove most of the solvent, the residue wasre-dissolved in EtOAc and washed with saturated NaHCO₃ and brine. Theorganic layer was dried over anhydrous MgSO₄ and concentrated to givethe N-ethyl derivative as an orange solid.

[0993] This solid was dissolved in THF (2.5 mL), DBU (113 mg, 0.74 mmol)was added and the mixture was stirred at room temperature for 30 min.The solvent was evaporated, the remaining residue was dissolved in EtOAcand the organic layer was washed with saturated NaHCO₃ and brine. Theorganic layer was further extracted with 1N HCl and H₂O (2×), and the pHof the combined aqueous layers was adjusted to pH ˜10 with 1 N NaOH. Theaqueous layer was then extracted with EtOAc (3×), the combined organiclayers were washed with brine, dried over anhydrous MgSO₄ andconcentrated to dryness to give the title amine derivative of example 28(44 mg): MS (ES⁺) m/z 373.1 (MH⁺).

[0994] A similar reductive amination procedure was used to prepare otherN-alkylated pyrrolidine (e.g. cucurbitine) and piperidine derivatives.Alternatively, the reductive amination can be performed as the last stepon a fully assembled inhibitor.

Example 29 General Procedure for Coupling amines to 6-indole carboxylicacids to give amide derivatives of General Formulae I

[0995] Indole carboxylic acids were coupled to various amines (forexample according to the examples 15a, 15b, 15c, 19, 20, 21, 22,23, 24,25, 28, 34, 35, 36, 42,43, or 45) using standard amide bond formingprocedures familiar to those skilled in the art. Amide bond formingreagents include but are not limited to carbodiimides (DCC, EDC), TBTU,HBTU, HATU and BOP-CI in the presence or absence of additives such asHOBt or HOAT. Indole carboxylic acids can also be activated for couplingby conversion to the corresponding acid chloride, symmetrical anhydrideor unsymmetrical anhydrides using standard protocols familiar to thoseskilled in the art of organic chemistry. The coupling of indolecarboxylic acids with amines is generally carried out in solvents suchas THF, DCM, DMF, DMSO or MeCN, in the presence of a tertiary organicbase including, but not limited to triethylamine, N-methylmorpholine,collidine and diisopropylethylamine. Following coupling of the indolecarboxylic acid with the amine, any remaining protecting group thatremains in the molecule can then be removed using the appropriateprocedure. The following example serves to illustrate such a process andis non-limiting.

[0996] The indole carboxylic acid of example 9 (0.030 g, 0.069 mmol, 1equiv.), the amine of example 21 (0.044 g, 0.153 mmol, 2.2 equiv.) andTBTU (0.076 g, 0.24 mmol, 3.4 equiv.) were dissolved in DMSO (2 mL) andtriethylamine (84 μL, 0.6 mmol, 8.7 equiv.) was added. The mixture wasstirred overnight at room temperature (complete by HPLC). 3N NaOH (0.7mL) was added and the mixture stirred at 50° C. for 40 min (completehydrolysis by HPLC). Acetic acid was added to neutralize the reactionmixture and the product was isolated directly by preparative HPLC as abeige amorphous solid (19 mg).

Example 30 General Procedure for the Preparation of indole6-acylsulfonamide derivatives

[0997] Indole carboxylic acids were converted to the corresponding acidchloride and coupled to various sulfonamides in the presence of DMAP andan organic base such as triethylamine, DIEA, N-methylmorpholine and thelike. Alternatively, the carboxylic acid was activated using amide bondforming agents such as carbodiimides (DCC, EDC), TBTU, HATU and the likeand treated with sulfonamides in the presence of DMAP. Sulfonamides wereeither from commercial sources or prepared from the correspondingsulfonyl chlorides and a solution of ammonia in dioxane.

[0998] The following example serves to illustrate such as process and isnon-limiting.

3-Cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yl-2oxo-ethyl)-1H-indole-6-carboriyl chloride

[0999] The carboxylic acid of example 9 (0.800 g, 1.833 mmol, 1 equiv.)was suspended in DCM (15 mL) and DMF (20 μL) was added followed byoxalyl chloride (323 μL, 3.7 mmol, 2 equiv.). After stirring for 2 h atroom temperature, volatiles were removed under reduced pressure and theresidue co-evaporated twice with DCM. After drying under vacuum for 1.5h, the acid chloride was obtained as a brown solid that was useddirectly in the next step.

4-Bromo-N-{1-[3-cyclohexyl-2-furan-3-yl-1-(2-morpholin-4-yi-2-oxo-ethyl)-1H-indole-6-yl]-methanoyl}-benzenesulfonamide

[1000] The acid chloride from above (0.032 g, 0.07 mmol, 1 equiv.) wasdissolved in DCM (2 mL) and 4-bromobenzenesulfonylamide (0.0205 g, 0.085mmol, 1.2 equiv.) was added. Triethylamine (21 μL, 0.15 mmol, 2.16equiv.) and DMAP (0.018 g, 0.147 mmol, 2.1 equiv.) were added and themixture was stirred overnight at room temperature (complete by HPLC).DCM was then evaporated in air and the residue re-dissolved in DMSO (2mL). The title compound of example 30 was isolated directly bypreparative HPLC as a light yellow powder (27 mg).

Example 31

[1001]

[1002] The N-methylacylsulfonamide of example 31 was prepared from theacid chloride described in example 30 and N-methylbenzenesulfonamideusing the procedure of example 30.

Example 32

[1003]

[1004] Acetamide (9 mg, 0.152 mmol, 1.38 equiv.) was dissolved in THF (2mL) and NaH (60% oil dispersion, 8 mg, 0.2 mmol, 1.81 equiv.) was added.The mixture was stirred for 30 min and the acid chloride of example 30(0.050 g, 0.11 mmol, 1 equiv.) in THF (1 mL) was added. The reactionmixture was then stirred for 2 h at room temperature (complete by TLC).The reaction was diluted with EtOAc and the solution washed with 10%aqueous HCl and dried (Na₂SO₄). After evaporation of the solvent underreduced pressure, the residue was purified by flash chromatography onsilica gel using EtOAc as eluent. The title compound of example 32 wasobtained as a white solid (24 mg).

Example 33

[1005]

[1006] Using the same series of reactions described in example 2 butstarting from indole 5-carboxylic acid, the title compound of example 33was obtained. This compound is a starting material for the synthesis ofcompounds according to the general formula 1.4, whereby the methods asdescribed hereinbefore, e.g. 4 to 8 and/or in combination with 9 to 32,can be employed in an analogous manner.

Example 34

[1007]

[1008] Methyl 4-hydroxybenzoate (20.00 g, 131 mmol) was dissolved in DMF(350 mL) and K₂CO₃ (24.19 g, 175 mmol) was added. The mixture wasstirred for 30 min and crotyl bromide (85%, 16.47 mL, 160 mmol) wasadded dropwise over 4 min. The resulting amber suspension was stirredfor 4 h at room temperature. It was then poured into DCM and thesolution washed with water and brine. The extract was dried (MgSO₄) andevaporated to a pale yellow oil consisting of a mixture of two isomericallyl ether (4:1 ratio). Upon standing at room temperature, the oilpartially crystallized. The supernatant was decanted and the crystalswashed with hexane to provide 12.5 g of the desired ether as whitecrystals.

[1009] The above material (10.30 g, 50 mmol) was added to a flask heatedto 230° C. in a sand bath and the melted oil was stirred for 25 min atthat temperature. The material was then brought back to room temperatureand the resulting waxy solid used without purification in the next step.

[1010] The rearranged phenol from above (10.00 g, 48.5 mmol) wasdissolved in MeOH and the solution cooled to −78° C. in a dryice-acetone bath. Ozone was bubbled through the solution until completedisappearance of starting material (TLC). Dimethyl sulfide (7 mL) wasthen added dropwise at −78° C. and the mixture stirred for 10 min at−78° C. and at room temperature for 30 min. Volatiles were removed underreduced pressure, the residue was dissolved in ether and the solutionwashed with water (2×) and brine. After drying (MgSO₄) and removal ofvolatiles, the crude product which consists of a mixture of aldehyde andlactol was obtained as a milky oil (9.9 g).

[1011] The crude product from above (9.9 g, 48 mmol) was suspended in85% phosphoric acid (40 mL) and heated to 50° C. for 50 min after whicha white solid precipitated. Water (50 mL) was added and the solidcollected by filtration. The material was then dissolved in EtOAc andwashed with saturated aqueous NaHCO₃ and water. The solution was dried(MgSO₄) and concentrated to yield a residue that was purified by flashchromatography on silica gel using 10% EtOAc-hexanes as eluent. Thedesired benzofuran derivative was obtained (2.39 g).

[1012] The benzofuran derivative from above (2.20 g, 11.6 mmol) wasdissolved in THF (65 mL) and the solution cooled to −78° C. A solutionof lithium diisopropylamide (LDA, 2M in heptahe/THF/ethylbenzene, 6.9mL) was added dropwise over 10 min. After stirring for 35 min,cyclobutanone (1.793 mL, 24 mmol) was added dropwise and stirringcontinued at −78 ° C. for 15 min. The reaction mixture was then warmedto room temperature and quenched with 1N HCl. The product was extractedwith EtOAc, washed with water and brine and dried (Na₂SO₄). Purificationby flash chromatography on silica gel using 25% EtOAc in hexanes gavethe desired cyclobutyl carbinol (1.39 g) as a clear gum.

[1013] The alcohol from above (1.38 g, 5.3 mmol) and sodium azide (1.105g, 17 mmol) were suspended in CHCl₃ (30 mL) and the mixture cooled inice. TFA (1.695 mL, 22 mmol) was added dropwise over 10 min, the coolingbath was removed and the mixture stirred at room temperature for 20 min.The reaction mixture was diluted with CHCl₃, washed with saturatedaqueous NaHCO₃ and dried (MgSO₄). Removal of solvents under reducedpressure gave a amber oil that was purified by flash chromatography onsilica gel using 5% EtOAc in hexane as eluent. The desired azide wasobtained as a clear oil (882 mg).

[1014] The azide from above (880 mg) was hydrogenated (1 atm H₂) in MeOHover 5% Lindlar catalyst (374 mg). After 15 min, the reduction wasjudged complete by TLC. Removal of the catalyst by filtration andsolvent under reduced pressure gave the desired amine derivative ofexample 34 (785 mg) as a colorless oil: ES−MS: m/z 243 (M-NH₂).

Example 35

[1015]

[1016] Indole 6-carboxylic acid (10.00 g, 62 mmol) was esterified byrefluxing overnight in a mixture of MeOH (200 mL) and conc. H₂SO₄ (1mL). After cooling, the reaction mixture was poured into sat. aqueousNaHCO₃ and extracted with EtOAc. The extract was washed with aqueousNaHCO₃ twice and water. Drying (MgSO₄) and removal of volatiles gave thedesired methyl ester as a brown oil (10.4 g). The ester from above(10.40 g, 62 mmol) was dissolved in DMF (80 mL) and the solution cooledin ice. Sodium Hydride (60% oil dispersion, 2.852 g, 71.3 mmol) wasadded in small portions and the mixture was stirred at room temperaturefor 40 min. The reaction mixture was brought back to 0° C. andpara-toluenesulfonyl chloride (14.49 g, 76 mmol) was added. The mixturewas stirred for 2 h at room temperature. The reaction mixture was thendiluted with EtOAc, washed consecutively with 10% citric acid (2×),NaHCO₃ (2×) and brine. After drying (MgSO₄), removal of solvent gave abeige residue that was triturated twice with ether-hexanes (7.7 g).Concentration of mother liquors and trituration of the residue with MeOHgave an additional 5.8 g of the desired tosylated indole.

[1017] The material from above (1.750 g, 5.31 mmol) was dissolved in DCM(40 mL) and the solution cooled to −78° C. Diisobutylaluminum hydride(1M in DCM, 12.72 mL, 12.72 mmol) was added dropwise and the mixturestirred for 30 min at −78° C. The reaction mixture was then warmed toroom temperature, quenched with aqueous potassium sodium tartrate andstirred overnight at room temperature. The organic phase was decanted,washed with brine and dried (MgSO₄). Removal of volatiles andpurification by flash chromatography on silica gel gave the desiredalcohol as a colorless oil (1.35 g).

[1018] The alcohol from above (1.250 g, 4.15 mmol) was dissolved in THF(150 mL) and the solution was cooled to −78° C. Lithium diisopropylamide(2M in THF/heptane/ethyl benzene, 10.37 mL) was added dropwise over 5min. After stirring for an additional 30 min at −78° C., cyclobutanone(1.55 mL, 20.7 mmol) was added and the reaction mixture allowed to warmup to 0° C. The reaction was quenched with 10% citric acid and THFremoved under reduced pressure. Water was added and the product wasextracted with EtOAc, washed with aqueous NaHCO₃ and brine, and dried(MgSO₄). The material was purified by flash chromatography on silica gelusing 30-50% EtOAc in hexanes as eluent. The desired cyclobutyl carbinolwas obtained as an oil (0.94 g).

[1019] The alcohol from above (0.870 g, 2.34 mmol) was dissolved in DCM(20 mL) and 1,1,1-tris(acetyloxy-1,1-dihydro-1,2-benzodioxol-3-(1 H)-one(Dess-Martin periodinane) (1.060 g, 2.50 mmol) was added. The mixturewas stirred at room temperature for 3 h, quenched with aqueous NaHCO₃and extracted with EtOAc. The extract was washed with brine, dried(MgSO₄) and concentrated to give the desired aldehyde as an oil that wasused directly in the next step.

[1020] The crude aldehyde (assume 2.34 mmol) from above was dissolved inDCM (20 mL) and (carbethoxymethylene)triphenylphosphorane (0.871 g, 2.5mmol) was added. The mixture was refluxed for 4 h, concentrated and theproduct isolated by flash chromatography on silica gel using 20-30%EtOAc in hexanes as eluent. The desired cinnamate was obtained as a foam(0.400 g).

[1021] The cinnamate derivative from above (0.400 g, 0.9 mmol) wasdissolved in CHCl₃ (15 mL) and sodium azide (138 mg, 2.1 mmol) wasadded. TFA (0.39 mL, 5.1 mmol) was added dropwise over 5 min and themixture was then stirred at 60° C. for 4 h. The reaction mixture wasdiluted with CHCl₃, washed with aqueous NaHCO₃ and dried (MgSO₄). Theproduct was purified by flash chromatography on silica gel using 20%EtOAc in hexane as eluent, to give the desired azide as a yellow foam(0.207 g).

[1022] The azide from above (0.183 g) was dissolved in THF (5 mL)containing 1% water and triphenylphosphine (180 mg) was added. Themixture was stirred at 60° C. for 20 h and the final product of example35 isolated by preparative reversed-phase HPLC (42 mg).

[1023] This amine was coupled in the usual manner to indole carboxylicacid derivative to give final inhibitors after cleavage of the N-tosyland ester protecting groups with NaOH.

[1024] Final products obtained as above were also methylated on theindole nitrogen by treating the fully deprotected molecules with NaH andiodomethane, followed by saponification of the methyl ester which wasformed concomitantly.

Example 36

[1025]

[1026]2-Ethoxy-4-nitrobenzoic acid (1.56 g; 7.38 mmol) was dissolved inmethanol (15 mL) and the resulting solution stirred at 0° C. A solutionof diazomethane in ethyl ether was slowly added until the yellow colorpersisted and was stirred for a further 20 min. The solvents wereevaporated to afford the methyl ester as a pale yellow solid (1.66 g,quant.) which was used without further purification.

[1027] The ester from above (1.60 g; 7.10 mmol) was dissolved in drytoluene and the solution cooled to −78° C. under a nitrogen atmosphere.A solution of diisobutylaluminum hydride in tetrahydrofuran (1M; 8 mL; 8mmol) was added and the reaction allowed to warm to ambient temperature.Two additional portions of DIBAL-H were added in this way (7 and 10 mL)after 1 h and a further 1.5 h. 0.5 h after the last addition, thereaction was cooled to 0° C. and 1N HCl (25 mL) was slowly added and themixture stirred vigorously for 0.5 h. The organic solvents were thenevaporated and the aqueous residue was extracted with ethyl acetate(2×50 mL) and washed with water (50 mL) and brine (50 mL). The combinedextracts were then dried over MgSO₄ and evaporated to afford the alcoholas a pale yellow, fibrous solid (1.40 g; quant.) which was used as such.

[1028] A turbid solution of 1,1,1-tris(acetyloxy-1,1-dihydro-1,2-benzodioxol-3-(1 H)-one (Dess-Martin periodinane) (2.32 g;5.47 mmol) in dichloromethane (40 mL+5 mL rinse) was added to a stirredsolution of the above alcohol (0.98 g; 4.97 mmol) in DCM (40 mL) and thereaction stirred at ambient temperature under a nitrogen atmosphere.After 4 h, saturated NaHCO₃/10% Na₂S₂O₃ (1:1, 160 mL) was added and themixture stirred vigorously until the phases were clear (ca. 0.5 h). Theorganic phase was separated and the aqueous phase was extracted withdichloromethane (50 mL) and washed with saturated NaHCO₃ (2×150 mL). Thecombined organic phases were then dried over MgSO₄ and evaporated toyield the aldehyde as a pale yellow solid (960 mg; 99%) which was usedas such. Sodium hydride (95% dry powder; 158 mg; 6.25 mmol) wassuspended in anhydrous THF (10 mL) and trimethyl phosphonoacetate (0.945mL; 5.84 mmol) added dropwise at 0° C. under a nitrogen atmosphereresulting in a solid white mass which could not be stirred. A solutionof the aldehyde from above (950 mg; 4.87 mmol) in THF (7 mL+3 mL rinse)was then added dropwise resulting in a yellow colour and slowdissolution of the white solid mass. After the addition, the reactionwas allowed to warm to ambient temperature. After 15 h, the cloudyreaction mixture was evaporated to a pale yellow solid which wasextracted with ethyl acetate (2×50 mL) and washed with saturated NaHCO₃(3×75 mL). The combined extracts were dried over MgSO₄ and evaporated toafford the cinnamate ester as pale yellow solid (1.212 g; 99%) which wasused without further purification.

[1029] The nitro cinnamate from above (0,300 g, 1.2 mmol) was suspendedin EtOH (12 mL) and water (7.5 mL) and K₂CO₃ (0.990 g, 7.16 mmol) and85% sodium hydrosulfite (1.247 g. 7.16 mmol) were added successively.The mixture was stirred vigorously at room temperature for 1.5 h. It wasthen diluted with water (10 mL) and the ethanol removed under reducedpressure. The reaction mixture was extracted with EtOAc (2×), washedwith water and brine and dried (MgSO₄). Removal of the solvent underreduced pressure gave the desired aniline as a yellow solid.

[1030] Note: the analogous methoxy derivative was prepared in the samemanner using commercially available 2-methoxy-4-nitrobenzoic acid asstarting material.

Example 37 3-(4,5-Diamino-2-alkoxy-phenyl)-acrylic acid methyl esters

[1031]

[1032] The procedures will be illustrated for R═Et but similar protocolscan be used to prepare derivatives with other alkoxy substituents.

[1033] The ortho-ethoxy-para-nitro cinnamate derivative prepared asdescribed in example 36 (600 mg; 2.39 mmol) was dissolved inconcentrated sulphuric acid (5.5 mL) at 0° C. and potassium nitrate (253mg; 2.50 mmol) added in portions over 3 min. After 5 min, the resultingyellow-brown solution was allowed to warm to ambient temperature and wasstirred under a nitrogen atmosphere. After 3 h, the reaction was addedto ice (75 g) resulting in a pale yellow precipitate. Once the ice hadmelted, the suspension was sonicated, filtered and washed several timeswith distilled water. Air drying overnight afforded the dinitrocinnamateas a pale yellow, chalky solid (661 mg; 93%) which was used withoutfurther purification.

[1034] The dinitrocinnamate (657 mg; 2.22 mmol) was dissolved/suspendedin ethanol/water (1:1; 40 mL) resulting in a yellow suspension which wasstirred vigorously at ambient temperature. Potassium carbonate (3.06 g;22.2 mmol) and sodium hydrosulfite (3.86 g; 22.2 mmol) were successivelyadded resulting immediately in a dark violet/green colour which quicklybegan to lighten to a pale orange. After 3 h, the reaction was dilutedwith water (20 mL) and the ethanol evaporated. The aqueous residue wasextracted with ethyl acetate (2×50 mL) and washed with saturated NaHCO₃(2×60 mL) and brine (30 mL). The combined extracts were dried overNa₂SO₄ and evaporated to afford the dianiline as a dark orange syrupwhich solidified under high vacuum (377 mg; 72%).

[1035] Such dianiline derivatives as described in this example could beconverted to benzimidazole derivatives by coupling to amino acidderivatives as described in example 22 to prepare inhibitors.

Example 38 3-(4-Amino-2alkyl-phenyl)-acrylic acid methyl esters and3-(4,5-diamino-2-alkyl-phenyl)-acrylic acid methyl esters

[1036]

[1037] As one skilled in the art would recognize, analogs of derivativespresented in examples 36 and 37 where the alkoxy group has been replacedby an alkyl, alkenyl or alkynyl substitutent (e.g. R=Me, Et, Pr, vinyl,allyl) can be prepared by converting such an alkoxy derivative (e.g.methoxy) to the corresponding phenol by cleaving the ether linkage withreagents such as BBr₃ and then converting the phenol substituent to thecorresponding triflate. Such triflates can then be used as substrates ina variety of transition metal catalyzed cross-coupling reactions withorganometallic reagents that would allow replacement of the triflatefunctionality by an alkyl substituent. Such reagents might includetetraalkyltin, tetraalkenyltin, alkylboronic acid and alkenylboronicacid derivatives that would undergo cross-coupling under Pd° catalysis.In some cases (e.g. allyl or vinyl), the substituent can be furtherelaborated (e.g. the double bond can be converted to a cyclopropane ringusing a cyclopropanating reagent known to people skilled in the art)

[1038] Once the alkyl group has been introduced, the intermediates canthen be elaborated to inhibitors following synthetic sequences describedin previous examples.

Example 391-Carboxymethyl-3-cyclohexyl-2-furan-3yl-7-methyl-1H-indole-6-carboxylicacid methyl ester

[1039]

[1040] Step 1: 3-amino4-methylbenzoic acid (15.00 g, 0.099 mol) wassuspended in MeOH (150 mL) and thionyl chloride (25.33 mL, 0.347 mol,3.5 equiv.) was added dropwise. The mixture was heated overnight at 70°C. After cooling to RT, volatiles were removed under reduced pressureand the residue triturated with ether (150 mL). The solid was filteredoff and dried (18.36 g). The solid was suspended in DCM (600 mL) andsaturated aqueous NaHCO₃ (250 mL) was added. After stirring for 15minutes, the organic layer was separated and washed successively withNaHCO₃ solution (2×250 mL), water (250 mL) and brine (250 mL). Thesolution was dried (Na₂SO₄), filtered and evaporated to dryness to givethe desired aniline (14.8 g, 90% yield).

[1041] Steps 2 and 3: the ester from above (12.50 g, 75.6 mmol) wasdissolved in DCM (190 mL) and methylthioaldehyde dimethyl acetal (10.1mL, 75.6 mmol) was added. The solution was cooled to −30° C.N-chlorosuccinimide (10.10 g, 75.6 mmol) was added in 6 portions over 30minutes. Triethylamine (10.6 mL, 75.6 mmol) was then added dropwise over10 min and after stirring for an additional 15 min, the cooling bath wasremoved and the temperature brought to reflux. After 5 h, the reactionmixture was cooled to RT and evaporated to dryness. The residue wasdissolved in ether (750 mL) and 2M HCl (303 mL) was added. Afterstirring at RT for 1.5 h, the ether layer was separated and washed withNaHCO₃ solution (2×150 mL) and brine (250 mL). The original acidicaqueous phase was extracted with DCM (2×100 mL) and the extracts washedas above and then combined with the first ether phase. The combinedorganic phases were dried (Na₂SO₄) and evaporated to dryness and thematerial purified by flash chromatography on silica gel using 30-0%hexane in DCM as eluent to give the desired 3-thiomethylindolederivative (9.37 g).

[1042] Step 4: the thiomethyl indole from above (8.37 g, 35.4 mmol) wasdissolved in absolute EtOH (220 mL) and Raney-nickel (Ra—Ni) (25 g) wasadded. After stirring at RT for 3 h, another portion of Ra—Ni (15 g) wasadded and stirring resumed for an additional 45 min. The mixture wasfiltered and the filtrate evaporated to dryness to give the desiredindole (6.26 g, 93%).

[1043] Steps 5: the indole ester from above (4.00 g, 21 mmol) wasdissolved in a mixture of MeOH (18 mL) and water (18 mL). KOH (11.86 g,210 mmol) was added and the mixture stirred at 75° C. for 2 h.Cyclohexanone (7.26 g, 74 mmol, 3 equiv.) was added dropwise over 15 minand stirring at 75° C. was continued overnight. MeOH was removed underreduced pressure and water (500 mL) was added to the residue. Insolublematerial was removed by filtration and the aqueous phase was then washedwith TBME (200 mL). The aqueous phase was acidified to pH 4 with formicacid to produce a white precipitate that was collected by filtration,washed with water and dried. The desired cyclohexenylindole was obtained(4.77 g, 89%).

[1044] Steps 6-8: as described in example 2.

[1045] Steps 9-11: as described in examples 4 and 6.

Example 40

[1046]

[1047] Step 1: 4-methylsalicylic acid (100 g, 0.66 mol) was dissolved inacetone (1 L) and K₂CO₃ (227 g, 1.64 mol, 2.5 equiv.) was added inportions. The mixture was heated to reflux and dimethylsulfate (155 mL,1.64 mol, 2.5 equiv.) was added dropwise over 1 h. The mixture wasrefluxed overnight. Additional K₂CO₃ (90 g) and dimethylsulfate (60 mL)were added and the mixture refluxed for an additional 20 h. K₂CO₃ (20 g)and dimethylsulfate (15 mL) were again added and after refluxing for 7h, the reaction was judged complete by TLC. Solids were removed byfiltration using acetone for washings and the filtrate concentrated to avolume of 200 mL. The solution was diluted with MeOH (1 L) and stirredwith ammonium hydroxide (300 mL) for 30 min. MeOH was removed underreduced pressure and the residue extracted with EtOAc (2×400 mL). Theextract was washed with brine (500 mL) and dried (Na₂SO₄). Removal ofvolatiles gave the desired product as a yellow oil (119 g).

[1048] Step 2: the ester from above (117 g, 0.649 mol) was charged in aflask cooled in ice. The ester was dissolved in conc. H₂SO₄ (600 mL) andthe solution cooled to −3+ C. Conc. HNO₃ (51 mL) was added dropwise over1.5 h keeping the internal temperature around 0° C. The ice bath wasremoved and the mixture stirred at RT for 3.5 h. The reaction mixturewas poured over ice and allowed to stand overnight. The precipitatedsolid was collected by filtration, washed with water and dried. Thematerial was purified by trituration from hot methanol and flashchromatography on silica gel to separate the desired product from adinitro side product.

[1049] Step 3: The nitro ester from above (75.7 g, 0.336 mol) wasdissolved in DMF (322 mL) and DMF dimethylacetal (120.1 g, 1.01 mol) wasadded dropwise over 10 min. The mixture was heated to 115° C. for 3 h(complete by TLC). The reaction mixture was cooled to RT and volatilesremoved under vacuum. The residue was co-evaporated twice with DCM andtriturated with ether to give a total of 90.02 g (95% yield) of thedesired enamine derivative.

[1050] Step 4: The enamine from step 3 (90.02 g, 0.321 mol) wasdissolved in 1:1 THF-MeOH (1.48 L) and the mixture heated to 35° C. in awater bath. Raney nickel (washed with THF, 6.3 g) was added followed bydropwise addition of hydrazine (18.5 g, 0.369 mol) over 15 min. Afterstirring for 1 h (internal temperature: 49° C.), a second portion ofhydrazine (18.5 g) was added dropwise and the mixture stirred overnightat 49° C. Evaporated solvent was replenished and Raney-nickel (6.3 g)and hydrazine (18.5 g) were again added followed by another portion ofhydrazine (18.5 g) after stirring for an additional 3 h. After stirringat 54° C. overnight, the reaction was completed by addition of a lastportion of Raney-nickel (6.3 g) and hydrazine (36 mL) and stirring 20 h.The reaction mixture was then brought back to RT and filtered using DCMfor washings. The filtrate was evaporated to dryness under reducedpressure and the residue purified by flash chromatography on silica gelusing 2-30% EtOAc in DCM as eluent. The desired indole was obtained(41.1 g). The indole from step 4 was elaborated to the title compound ofexample 40 using procedures similar to those described in the previousexample.

Example 413-Cyclohexyl-2-furan-3-yl-5-hydroxy-1-[2-oxo-2-(4-pyrrolidin-1yl-piperidin-1-yl)-ethyl]-1H-indole-6-carboxylicacid

[1051]

[1052] This is a representative procedure that can be applied to analogswith other amide substituents: the methoxyindole (30 mg) was dissolvedin DCM (1 mL) and the solution was cooled in ice under a nitrogenatmosphere. Boron tribromide (1M in DCM, 0.3 mL) was added dropwise andthe mixture was stirred for 40 min at 0° C. and then 30 min at RT. Thereaction was then quenched by addition of ice, diluted with DCM andneutralized by addition of solid NaHCO₃. The organic phase was separatedand dried (MgSO₄). Evaporation of the solvent under reduced pressuregave the desired phenol derivative as a yellow solid (21 mg) that wassaponified to give the title compound of example 41 under standardconditions. Alternatively, the intermediate phenolic ester can bealkylated under standard conditions (e.g. NaH in DMF) to produce variousether derivatives (e.g. with tert-butyl bromoacetate)

Example 42 1-(2-Methyl-thiazol-4-yl)-cyclobutylamine hydrochloride

[1053]

[1054] Step 1: The starting protected amino acid was obtained using asimilar procedure to that described in example 21 but using benzylalcohol instead of trimethylsilyl ethanol in the curtius rearrangement.The acid (7.48 g, 30mmol) was dissolved in THF (50 mL) and the solutioncooled to −8° C. under a nitrogen atmosphere. N-Methylmorpholine (3.63mL, 33 mmol) was added dropwise followed by isobutylchloroformate (3.89mL, 30 mmol). The suspension was stirred for 10 min and filtered undernitrogen, keeping the filtrate at −8° C. The solution was then added toan excess ethereal diazomethane solution and the mixture stirred for 30min (TLC shows complete conversion to the diazomethylketone). 48% HBr inwater (3.50 mL, 31 mmol) was then added dropwise over 5 min to the coldsolution. A second portion of HBr (3.5 mL) was added after 5 min, thecooling bath was removed and the mixture stirred at RT overnight. Ether(250 mL) was added and the solution washed with water (2×50 mL),saturated NaHCO₃ (50 mL) and brine (50 mL). After drying (MgSO₄),volatiles were removed under reduced pressure and the residue trituratedwith 1:4 ether/hexanes. The white solid was filtered, washed with hexaneand dried in vacuum. The desired bromomethylketone (7.35 g, 75% yield)was obtained as a white solid.

[1055] Step 2: The bromomethylketone from above (228 mg, 0.7 mmol) andthioacetamide (56.3 mg, 0.75 mmol) were heated to reflux in isopropanol(5 mL). After 1 h, the reaction mixture was evaporated to dryness andthe oily residue triturated with water to give a white precipitate thatwas collected, washed with water and dried in vacuum (185 mg, 87%yield).

[1056] Step 3: 10% Pd on charcoal (70 mg) was suspended in EtOH (5 mL)and the protected thiazole derivative from above (180 mg) was added.Hydrochloric acid was added to acidify the reaction mixture which wasthen stirred under 1 atm of H₂ gas for 20 h. The catalyst was removed byfiltration and the filtrate evaporated to dryness under reduced pressureto give the desired amine hydrochloride as a white solid (104 mg) aftertrituration with ether.

[1057] The amine hydrochloride was coupled to indole derivatives understandard conditions.

[1058] Note: Analogous thiazole derivatives can be prepared in a similarway by using differently substituted thioamide, thiourea or acylthioureaderivatives. In addition, other protected amino acids can be used asstarting materials in this sequence and converted to their respectivebromo or chloromethylketones to be used in turn to prepare varioussubstituted thiazole derivatives.

Example 43

[1059]

[1060] The 4-nitro-2-ethoxycinnamate (303 mg, 1.206 mmol), prepared asdescribed in example 36 was dissolved in concentrated sulfuric acid ( 3mL) and the solution cooled to 0° C. Potassium nitrate (128 mg, 1.27mmol) was added and the mixture stirred for 3.5 h at room temperature.After completion, the reaction mixture was poured over ice and theprecipitated solid was collected by filtration. The crude product waswashed with water, dried under vacuum and used without purification inthe next step (390 mg).

[1061] The dinitro derivative from above (390 mg) was dissolved in THF(3 mL) and methylamine in THF (3.02 mL of a 2M solution in THF) wasadded. After stirring for 30 min, volatiles were removed under reducedpressure and the orange solid used as such in the next step.

[1062] The nitro arene from above was suspended in a mixture of EtOH (12mL) and water (12 mL) and K₂CO₃ (1.00 g, 6 equivalents ) was addedfollowed by sodium hydrosulfite (1.26 g, 6 equivalents). The mixture wasstirred for 4 h at room temperature and EtOH was removed under reducedpressure. The residue was extracted with EtOAc and the organic phasewashed with brine and dried (MgSO₄). Removal of the solvent andpurification of the residue by flash chromatography (50 to 75% EtOAc inhexane) gave the desired diamine (162 mg).

[1063] The dianiline from above (162 mg) was dissolved in acetonitrile(6 mL) and aminocyclobutanecarboxyl chloride hydrochloride prepared asin example 20 (116 mg) was added. The mixture was stirred overnight atroom temperature, diluted with EtOAc and the solution washed withaqueous NaHCO₃ and brine. After drying (MgSO₄), volatiles were removedunder reduced pressure. The residue was dissolved in AcOH (3 mL) and thesolution heated to 80° C. for 1 h. After cooling to room temperature,the reaction mixture was poured into water and basified to pH 9 byaddition of solid K₂CO₃. The organic phase was then extracted withEtOAc, washed with brine and dried (MgSO₄). Removal of the solvent gavea residue that was purified by flash chromatography on silica gel using0 to 5% MeOH in EtOAc to give the title compound of example 43 (68 mg).

Example 44

[1064]

[1065] Step 1: 4-methylsalicylic acid (32.1 g, 0.21 mol) and potassiumcarbonate (61.2 g, 0.44 mol) were suspended in acetone (300 mL) and themixture brought to reflux temperature. Dimethyl sulfate (66.5 g, 0.53mol) was added dropwise within 1 h and stirring continued overnight atreflux. Additional dimethylsulfate (30 mL) and potassium carbonate (2×15g) were added and refluxing for an additional 24 h was required tocomplete the reaction. The reaction mixture was then cooled to roomtemperature and inorganic salts removed by filtration using acetone forwashings. The filtrate was evaporated under reduced pressure and theoily residue was dissolved in MeOH (300 mL). Concentrated ammoniumhydroxide (90 mL) was added and the mixture was stirred for 30 minutesat room temperature. Methanol was removed in vacuo and the residueportioned between ether (300 mL) and water (200 mL). The organic phasewas separated and washed with brine and dried (Na₂SO₄). Evaporation ofthe ether gave the desired di-methylated product as a yellow oil (38.1g) that was used directly in the next step.

[1066] Step 2: The ester from above (38.0 g, 0.21 mol) was dissolved inAcOH (250 mL) and bromine (37.2 g, 0.23 mol, 1.1 equiv.) was addeddropwise over 30 min with stirring at room temperature. Aftercompletion, the reaction mixture was stirred for an additional hour, atwhich point TLC analysis indicated complete conversion. The reactionmixture was poured into water (1 L) and solid Na₂CO₃ was addedcautiously with stirring until the mixture was neutral. The off-whiteprecipitate that formed was collected by filtration, washed with waterand dried to give the desired bromo derivative (47.2 g).

[1067] Step 3: The bromo derivative from above (44.5 g, 0.17 mol) wasadded in small portions to conc. H₂SO₄ (170 mL) and the mixture wasstirred in an ice-salt bath until all solids dissolved. Conc. HNO₃ (17mL) was then added dropwise over 20 min and stirring continued for anadditional hour in the ice bath. The reaction mixture was then slowlyadded to ice-water (2 L) and the precipitated yellow solid was collectedby filtration. The solid was washed with water, NaHCO₃ solution andwater again. After drying, the desired nitro derivative was obtained asan orange solid (36.8 g).

[1068] Step 4: The product from above (129.0 g, 0.42 mol) was dissolvedin DMF (400 mL) and DMF-dimethyl acetal (151.6 g, .1.27 mol, 3 equiv.)was added in one portion. The mixture was heated at 110-120° C. under anargon atmosphere until conversion was judged complete by TLC (24 h). Thereaction mixture was cooled to room temperature and volatiles removedunder vacuum to give a dark colored residue (˜180 g). Trituration fromether-THF gave the desired enamine as red crystals (72 g).

[1069] Step 5: The enamine from above (72.0 g, 0.20 mol) was dissolvedin a mixture of THF (600 mL) and MeOH (600 mL). The dark red solutionwas heated to 30° C. and Raney-Nickel (18 g) was added to the solution.Hydrazine hydrate (11.6 g, 0.23 mol, 1.15 equiv.) was then addeddropwise over 30 min. The reaction temperature was increased to 50° C.and a second portion of hydrazine hydrate (11.6 g, 0.23 mol, 1.15equiv.) was added over 30 min. After stirring overnight at 50° C.,additional Raney-nickel (20 g) and hydrazine hydrate (11.6 g, 0.23 mol,1.15 equiv.) were added and after stirring for another 7 h at 50° C.,the reaction was judged complete by TLC. After cooling, the catalyst wasremoved by filtration through a pad of celite and the filtrate wasevaporated under reduced pressure. The dark brown residue was dissolvedin EtOAc (3 L) and the solution washed with water (1.5 L), 10% HCl (1 L)and brine (700 mL). After drying (Na₂SO₄), removal of solvents gave thedesired bromoindole derivative as a brown solid (35 g).

[1070] Step 6: The bromoindole derivative from above (35 g) wasdissolved in MeOH (1 L) and triethylamine (16.3 g, 1.2 equiv.) was addedfollowed by 10% Pd/C (1.06 g).

[1071] The mixture was stirred under hydrogen (35 psi) until completionof the reaction (7 h). The catalyst was then removed by filtration andvolatiles removed under reduced pressure. The residue was dissolved inEtOAc (700 mL) and the solution washed with 10% HCl (300 mL), water (350mL), NaHCO₃ (350 mL) and brine. The solution was dried (Na₂SO₄) andconcentrated under reduced pressure to give the desired indole as alight brown solid (25 g).

[1072] This indole derivatives was saponified under standard conditionsand elaborated to final inhibitors as previously described for analogousderivatives.

Example 45

[1073]

[1074] Methyl 2-methoxy-5-nitrobenzoate (6.21 g, 29.4 mmol) wassuspended in MeOH (100 mL) and 20% Pd(OH)₂/C (500 mg) was added. Themixture was stirred under a hydrogen atmosphere (1 atm) for 18 h. Thecatalyst was removed by filtration and the solvent evaporated underreduced pressure (5.256 g).

[1075] The aniline from above (5.23 g) was dissolved in THF (50 mL) andacetic anhydride 2.984 g) was added. The mixture was stirred overnightat room temperature. The white suspension was concentrated under reducedpressure to a white paste, tert-butylmethyl ether (TBME, 20 mL) wasadded and while stirring, hexane (100 mL) was added slowly. Thesuspension was then stirred for an additional 2 h and the solidcollected by filtration. The product was washed with hexane and dried inair (6.372 g).

[1076] 90% Nitric acid (9 mL) was diluted with water (9 mL) and cooledto 0° C. The anilide from above (5.905 g) was added in one portion andthe mixture stirred for 30 min in the ice-water bath. The reactionmixture was then added dropwise to ice-water (700 mL) and theprecipitated yellow solid was collected by filtration, washed with waterand dried in air. The orange solid (5.907 g) was shown by ¹H NMR toconsist of a 2:1 mixture of compounds. Extraction of the aqueousfiltrate from above with EtOAc gave an additional 1 g of material thatwas combined with the first crop and purified by flash chromatography onsilica gel using 015% EtOAc in CHCl₃ as eluent. An orange solid (4.11 g)was obtained (one isomer).

[1077] The nitroanilide from above (3.580 g) was dissolved in THF (50mL) and the solution cooled in ice. lodomethane (4.155 mL, 66.7 mmol, 5equivalents) and sodium tert-butoxide (6.414 g, 66.7 mmol, 5equivalents) were added in two portions at a 3.5 h interval. Stirring atroom temperature was continued for an additional 20 h after the secondaddition. THF was evaporated under reduced pressure and water (100 mL)was added. The deep red solution was washed with TBME (100 mL). Theaqueous phase was acidified with conc. HCl and extracted with EtOAc(2×100 mL). The combined organic extracts were dried and concentrated toa dark red powder (3.78 g) that was used directly in the next step.

[1078] The free carboxylic acid (3.75 g) was suspended in 8M HCl (100mL) and the mixture stirred at 100° C. for 8 h. After cooling to roomtemperature, volatiles were evaporated under vacuum and the residue wasco-evaporated 3 times with MeOH. The residue was suspended again in MeoH(100 mL) and cooled in ice-water. Thionyl chloride (5.10 mL, 5equivalents) was added dropwise and the suspension stirred at 65° C. for4 h. Volatiles were removed under reduced pressure and the residueco-evaporated twice with MeOH (100 mL) and then toluene (2×100 mL). Theresidue was then dissolved in MeOH (200 mL), 20% Pd(OH)₂/C (500 mg) wasadded and the mixture stirred overnight under 1 atm of hydrogen gas. Thecatalyst was then removed by filtration and the solution evaporated todryness. The residue was dissolved in EtOAc and the solution washed withaqueous NaHCO₃ and dried (MgSO₄). Removal of solvents gave a solid thatwas suspended in TBME (50 mL) and heated to 60° C. for 30 min. An equalvolume of hexane was then slowly added to the hot solution and theprecipitated material was collected by filtration, washed withTBME-hexane and dried (2.00 g).

[1079] The diamine from above (1.950 g) was dissolved in DCM (50 mL) andthe solution cooled in ice. 1-Aminocyclobutyryl chloride hydrochlorideprepared using a similar procedure as in example 20 (1.50 g) was addedin 3 portions over a 1.5 h period. The mixture was then warmed to roomtemperature and stirred overnight. Additional acid chloride (0.50 g) wasadded and stirring continued for another 2 h. DCM was evaporated underreduced pressure and AcOH (30 mL) was added and the mixture heated to80° C. for 3 h. The reaction mixture was cooled to room temperature andvolatiles evaporated under reduced pressure. The residue was dissolvedin water (100 mL) and solid NaHCO₃ was added in portions until a pH of 8was reached. The product was then extracted with EtOAc (3×100 mL), dried(Na₂SO₄) and concentrated to dryness. The residue was purified by flashchromatography on silica gel using 0 to 15% EtOH in EtOAc as eluent. Thetitle compound of example 45 was obtained as a grey powder (1.05 g).

Example 46 Inhibition of NS5B RNA Dependent RNA Polymerase Activity

[1080] The compounds of the invention were tested for inhibitoryactivity against the hepatitis C virus RNA dependant polymerase (NS5B),according to protocol described in WO 03/010141

Example 47 Specificity of NS5B RNA Dependent RNA Polymerase Inhibition

[1081] The compounds of the invention were tested for inhibitoryactivity against polio virus RNA dependent RNA polymerase and calfthymus DNA dependent RNA polymerase 11 in the format that is describedfor the HCV polymerase with the exception that another polymerase wasused in place of the HCV NS5B polymerase as is described in WO 03/010141

[1082] In Tables 1 to 8 below, the following ranges apply: IC₅₀: A=10μM-1 μM; B=1 μM-200 nM; and C<200 nM. TABLE 1

wherein R³ is C_(n)-cycloalkyl and the index n is given in the table:Cpd. m/z # R² n L IC₅₀ (M + H)⁺ 1001

6

B 408.3 1002

6

C 561.2 1003

6

C 464.3 1004

6

C 486.2 1005

6

B 486.3 1006

6

B 437.2 1007

6

C 494.3 1008

6

C 423.2 1009

6

B 494.3 1010

6

C 518.3 1011

6

B 451.3 1012

6

C 453.2 1013

6

B 445.2 1014

6

B 483.2 1015

6

B 467.3 1016

6

C 492.3 1017

6

C 453.2 1018

6

A 489.3 1019

6

C 466.3 1020

6

C 465.2 1021

6

C 480.3 1022

6

B 466.2 1023

6

C 447.3 1024

6

C 514.4 1025

6

C 405.3 1026

6

B 419.3 1027

6

C 453.2 1028

6

C 411.2 1029

6

B 447.2 1030

6

C 437.3 1031

6

C 395.2 1032

6

B 409.3 1033

6

C 453.2 1034

6

C 520.3 1035

6

C 411.2 1036

6

B 425.2 1037

6

C 520.3 1038

6

C 504.3 1039

6

B 408.2 1040

6

B 537.2 1041

6

B 525.2 1042

6

B 503.2 1043

5

C 423.2 1044

5

C 381.1 1045

6

C 516.3 1046

6

A 461.2 1047

6

A 503.3 1048

6

B 570.3 1049

6

B 570.3 1050

6

C 530.3 1051

6

C 598.3 1052

6

C 655.3 1053

6

C M − H 636.3 1054

6

C 625.3 1055

6

C 531.2 1056

6

B 447.2 1057

6

C 464.2 1058

6

C 479.2 1059

6

C 487.2 1060

6

B 443.2 1061

6

B 487.2 1062

6

B 381.2 1063

6

B 457.2 1064

6

A 487.3 1065

6

B 367.2 1066

6

C 465.2 1067

6

C 425.2 1068

6

C 440.2 1069

6

B 536.2 1070

6

B 487.2 1071

6

B 513.2 1072

6

C 439.2 1073

6

C 439.2 1074

6

C 494.3 1075

6

C 501.2 1076

6

C 565.3 1077

6

C 625.3 1078

6

B 573.3 1079

6

C 625.3 1080

6

C 639.3 1081

6

C 570.3 1082

6

C 461.4 1083

6

B 609.4 1084

6

B 432.3 1085

6

B 446.3 1086

5

B 418.3 1087

5

B 432.3 1088

6

B 449.3 1089

6

B 463.3 1090

6

C 425.3 1091

6

B 491.4 1092

6

C 463.3 1093

6

B 477.4 1094

6

C 421.3 1095

6

B 512.3 1096

6

C 480.3 1097

6

C 437.3 1098

6

C 435.3 1099

6

C 479.3 1100

6

C 451.3 1101

6

B 449.3 1102

6

C 479.4 1103

6

C 486.3 1104

6

C 478.4 1105

6

B 486.3 1106

6

B 409.3 1107

6

B 425.3 1108

6

B 451.4 1109

6

B 515.3 1110

6

C 424.3 1111

6

C 395.3 1112

6

C 452.4 1113

6

B 451.3 1114

6

B 472.3 1115

6

A 471.3 1116

6

C 504.4 1117

6

B 500.3 1118

6

C 423.3 1119

6

C 453.3 1120

6

C 464.4 1121

6

C 466.3 1122

6

C 492.4 1123

6

B 465.3 1124

6

B 439.3 1125

6

C 478.4 1126

6

C 494.4 1127

6

C 535.3 1128

6

C 481.3 1129

6

C 481.3 1130

6

C 521.4 1131

6

C 464.4 1132

6

C 467.3 1133

6

B 620.2 1134

6

B 539.3 1135

6

B 568.3 1136

6

B 484.3 1137

6

B 554.3 1138

6

B 528.3 1139

6

C 583.3 1140

6

B 659.3 1141

6

B 654.3 1142

6

B 406.3 1143

6

A 392.2 1144

5

1145

5

1146

5

1147

6

1148

6

1149

1150

[1083] TABLE 2

m/z Cpd. # R^(N2) R^(C) IC₅₀ (M + H)⁺ 2001 H

C 576.3 2002 H

C 514.3 2003 H

C 590.3 2004 H

C 616.2 2005 H

C 568.2 2006 H

C 634.3 2007 H

C 626.3 2008 H

C 656.2 2009 H

C 606.3 2010 H

C 610.2 2011 H

C 656.2 2012 H

C 610.2 2013 H

C 660.3 2014 H

C 612.3 2015 H

C 594.3 2016 H

C 590.3 2017 H

C 677.3 2018 H

C 621.3 2019 H

C 610.2 2020 H

C 664.3 2021 H

C 655.3 2022 H

C 590.3 2023 CH₃

A 590.3 2024 H

C 627.3 2025 H

C 632.3 2026 H

C 540.2 2027 H

C 582.2 2028 H

C 636.3 2029 H

C 728.0 2030 H

C 650.1 2031 H

C 644.2 2032 H

B 601.2 2033 H

C 628.2 2034 H

C 595.3 2035 H

C 634.2 2036 H

C 612.2 2037 H

C 656.2 2038 H

C 654.3 2039 H

C 627.3 2040 H

C 620.3 2041 H

C 608.3 2042 H

C 656.3 2043 H

B 702.4 2044 H

C 618.3 2045 H

C 616.1

[1084] TABLE 3

wherein R³ is C_(n)-cycloalkyl and the index n is given in the table:Cpd. # R² n L

Q² IC₅₀ m/z (M + H)⁺ 3001

5

C 722.3 3002

6

C 736.4 3003

6

C 677.4 3004

6

C 548.3 3005

6

C 828.4 3006

6

C 691.5 3007

6

C 703.5 3008

6

C 674.4 3009

6

C 688.5 3010

5

C 660.4 3011

5

C 674.4 3012

6

3013

6

3014

6

3015

6

3016

6

3017

6

3018

6

3019

6

3020

[1085] TABLE 4

wherein R³ is C_(n)-cycloalkyl and the index n is specified in thetable: Cpd. m/z # R² n L Z IC₅₀ (M + H)⁺ 4001

6

A 460.4 4002

6

B 610.5 4003

6

C 599.4 4004

6

C 653.5 4005

6

C 607.5 4006

6

C 586.5 4007

6

B 540.5 4008

6

B 517.4 4009

6

B 560.4 4010

6

B 560.4 4011

6

B 529.3 4012

6

B 535.4 4013

6

B 583.4 4014

6

B 562.4 4015

6

B 540.4 4016

6

B 554.4 4017

6

B 540.4 4018

6

B 540.4 4019

6

B 521.4 4020

6

B 521.4 4021

6

B 539.4 4022

6

B 557.3 4023

6

B 569.4 4024

6

A 567.4 4025

6

B 520.4 4026

6

A 553.4 4027

6

B 547.4 4028

6

B 463.3 4029

6

C 571.4 4030

6

C 585.4 4031

6

B 567.4 4032

6

C 618.3 4033

6

A 567.3 4034

6

B 503.3 4035

6

B 554.4 4036

6

B 608.4 4037

6

A 581.4 4038

6

B 565.4 4039

6

B 553.4 4040

6

B 554.4 4041

6

C 617.4 4042

6

C 583.4 4043

6

C 583.4 4044

6

B 555.4 4045

6

B 570.3 4046

6

B 527.3 4047

6

B 526.3 4048

6

A 540.3 4049

6

B 450.3 4050

6

B 541.3 4051

6

B 570.4 4052

6

B 528.3 4053

6

B 485.3 4054

6

B 484.3 4055

6

B 498.3 4056

6

B 408.2 4057

6

B 499.3 4058

6

C 498.3 4059

6

C 528.3 4060

6

B 621.4 4061

6

B 563.3 4062

6

C 558.3 4063

6

B 600.3 4064

6

B 572.3 4065

6

A 540.2 4066

6

B 478.3 4067

6

C 676.3 4068

5

C 691.4 4069

6

C 705.4 4070

5

C 662.3 4071

6

B 542.2 4072

6

C 547.3 4073

6

B 562.2 4074

6

B 548.2 4075

6

B 536.3 4076

6

B 576.3 4077

6

C 521.3 4078

6

B 562.3 4079

6

B 561.3 4080

6

B 580.1 4081

6

C 588.4 4082

6

C 690.3 4083

6

C 566.3 4084

6

C 602.5 4085

6

C 565.1 4086

6

C 616.5 4087

6

C 522.2 4088

6

C 664.3 4089

6

C 614.3 4090

6

C 582.3 4091

6

B 547.3 4092

6

C 533.3 4093

6

C 561.3 4094

6

C 628.5 4095

6

C 642.5 4096

6

C 561.2 4097

6

C 573.4 (M − H)⁻ 4098

6

B 587.3 4099

6

C 654.3 4100

6

C 620.4 4101

6

B 731.4 4102

6

C 697.4 4103

6

C 669.4 4104

6

A 730.4 4105

6

B 697.4 4106

6

B 722.4 4107

6

C 668.4 4108

6

B 712.4 4109

6

C 581.2 4110

6

C 643.3 4111

6

B 587.3 4112

6

4113

6

4114

6

4115

6

4116

6

4117

6

4118

6

4119

6

4120

6

4121

6

4122

6

4123

6

4124

6

4125

6

4126

6

4127

6

4128

6

4129

6

4130

6

4131

6

4132

6

4133

6

4134

6

4135

6

4136

6

4137

6

4138

6

4139

6

4140

6

4141

6

4142

6

4143

5

4144

6

4145

6

4146

6

4147

5

4148

6

4149

6

4150

6

4151

6

4152

6

4153

6

4154

6

[1086] TABLE 5

wherein R³ is C_(n)-cycloalkyl and the index n is given in the table:Cpd. # R² n

Z IC₅₀ m/z (M + H)⁺ 5001

6

OH B 453.2 5002

6

OH B 451.2 5003

6

OH A 409.2 5004

6

OH B 350.2 5005

6

OH A 364.2 5006

6

OH A 378.2 5007

6

OH B 364.2 5008

6

OH A 451.2 5009

6

OH A 409.2

[1087] TABLE 6

m/z Cpd. # R² L Z IC₅₀ (M + H)⁺ 6001

B 437.2 6002

C 504.3 6003

B 395.2 6004

6005

6006

6007

[1088] TABLE 7

in the following table the index i indicates the position of the group—CO-Z and the index j indicates the position of the group R within thephenyl-ring. The term Me denotes methyl and Ph denotes phenyl. Cpd. m/z# L i Z j R IC₅₀ (M + H)⁺ 7001

2 OH 1 Me C 409.1 7002

2 OH 3 OMe B 467.2 7003

2 OH 3 OMe B 534.2 7004

2 OH 1 Me C 518.2 7005

2 OH 1 Me C 451.2 7006

2 OH 3 OMe B 425.1 7007

2 OH 3 OH A 520.2 7008

2 OH 3 OH A 453.2 7009

2 OH 3 OH A 411.1 7010

2 OMe 3 OH A 534.3 7011

2 OH 3 OCH₂COOH A 511.2 7012

3

— — A 633.4 7013

3

— — A 614.5 7014

3

— — A 600.5 7015

3

— — A 597.4 7016

3

— — A 587.4 7017

3

— — A 614.5 7018

3

— — A 664.5 7019

3

— — A 594.4 7020

3

— — A 622.5 7021

3

— — A 594.4 7022

3

— — A 658.5 7023

3

— — A 579.4 7024

3

— — A 623.5 7025

3

— — A 683.5 7026

3

— — A 607.5 7027

3

— — A 593.4 7028

3

— — A 653.5 7029

3

— — A 607.5 7030

3

— — A 621.5 7031

3

— — A 588.5 7032

3

— — A 686.5 7033

3

— — A 531.4 7034

3

— — A 517.4 7035

3

— — A 614.5 7036

3

— — A 645.4 7037

3

— — A 655.5 7038

3

— — A 705.4 7039

3

— — A 614.5 7040

3

— — A 662.5 7041

3

— — A 601.5 7042

3

— — A 679.4 7043

3

— — A 731.5 7044

3

— — A 615.5 7045

3

— — A 637.5 7046

3

— — A 616.5 7047

3

— — A 645.5 7048

3

— — A 703.5 7049

3

— — A 637.5 7050

3

— — A 677.5 7051

3

— — A 643.4 7052

3

— — A 609.5 7053

3

— — B 656.6 7054

3

— — A 643.5 7055

3

— — A 637.5 7056

3

— — A 651.5 7057

3

— — A 681.5 7058

3

— — A 503.3 7059

3

— — A 591.4 7060

3

— — A 699.4 7061

3

— — A 718.5 7062

3

— — A 746.5 7063

3

— — A 643.3 7064

3 OH — — 7065

3 NHSO₂Ph — — 7066

2 OH 3 OH 7067

2 OH 3 OMe 7068

2 OH 3 O—CH₂—Ph 7069

2 NHSO₂Ph 3 OH 7070

2 NHSO₂Ph 3 OMe 7071

2 NHSO₂Ph 3 O—CH₂—Ph 7072

2 OH 4 OH 7073

2 OH 4 OMe 7074

2 OH 4 NH₂ 7075

2 OH 4 NHCOMe 7076

2 OH 4 Cl 7077

2 OH 4 F 7078

2 OH 4 Me 7079

2 NHSO₂Ph 4 OH 7080

2 NHSO₂Ph 4 OMe 7081

2 NHSO₂Ph 4 NH₂ 7082

2 NHSO₂Ph 4 NHCOMe 7083

2 NHSO₂Ph 4 Cl 7084

2 NHSO₂Ph 4 F 7085

2 NHSO₂Ph 4 Me 7086

2 OH 1 Me 7087

2 OH 1 OH 7088

2 OH 1 OMe 7089

2 OH 1 Cl 7090

2 OH 1 F 7091

2 OH 1 COOH 7092

2 OH 1 CONH₂ 7093

2 OH 1 CONHMe 7094

2 OH 1 CONHCH₂Ph 7095

2 OH 1 NH₂ 7096

2 OH 1 NHCONHMe 7097

2 OH 1 NMe₂ 7098

2 OH 1 NHCOMe 7099

2 OH 1 NHCOCH₂Ph 7100

2 OH 1 NHCONH₂ 7101

2 NHSO₂Ph 1 Me 7102

2 NHSO₂Ph 1 OH 7103

2 NHSO₂Ph 1 OMe 7104

2 NHSO₂Ph 1 Cl 7105

2 NHSO₂Ph 1 F 7106

2 NHSO₂Ph 1 COOH 7107

2 NHSO₂Ph 1 CONH₂ 7108

2 NHSO₂Ph 1 CONHMe 7109

2 NHSO₂Ph 1 CONHCH₂Ph 7110

2 NHSO₂Ph 1 NH₂ 7111

2 NHSO₂Ph 1 NHCONHMe 7112

2 NHSO₂Ph 1 NMe₂ 7113

2 NHSO₂Ph 1 NHCOMe 7114

2 NHSO₂Ph 1 NHCOCH₂Ph 7115

2 NHSO₂Ph 1 NHCONH₂

[1089] TABLE 8

Cpd. # L Z 8001

8002

8003

8004

8005

8006

1. An isomer, enantiomer, diastereoisomer or tautomer of a compound,represented by formula I:

wherein: either A or B is N and the other B or A is C, wherein - - -between two C-atoms represents a double bond and - - - between a C-atomand a N-atom represents a single bond, the group —C(═Y¹)-Z is covalentlylinked to either M² or M³, M¹ is CR^(4a), M² or M³, when not linked to—C(═Y¹)-Z, is CR⁵, M⁴ is CR^(4b), and in addition one or two of thegroups selected from M¹, M², M³ and M⁴ may also be N, with the provisothat the group M² or M³ to which —C(═Y¹)-Z is linked is an C-atom, Sp isa spacer group selected from —(CR⁵¹R⁵²)_(k1)—, wherein k1 is 1, 2 or 3;R⁵¹, R⁵² are independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, or R⁵¹ and R⁵² are covalently bondedtogether and to the carbon-atom to which they are attached to form a 3,4, 5, 6 or 7-membered saturated or 5, 6 or 7-membered unsaturated cyclicsystem whereby the 5, 6 or 7-membered saturated or unsaturated cyclicsystem may contain 1 to 3 heteroatoms selected from N, O or S; saidalkyl, cycloalkyl, alkyl-cycloalkyl or cyclic system being optionallysubstituted by halogen, hydroxy, (C₁₋₆)alkoxy, cyano, amino,—NH(C₁₋₄-alkyl) and/or —N(C₁₋₄-alkyl)₂; Y⁰ is O, S, NR¹¹ or CR¹²R¹³,wherein R¹³, R¹², R¹³ are each independently defined as R^(O); R¹³ mayalso be COOR^(O) or SO₂R^(C); wherein R^(C) and each R^(O) is optionallysubstituted with R¹⁵⁰; or both R¹² and R¹³ are covalently bondedtogether and to the carbon-atom to which they are attached to form a 3,4, 5, 6 or 7-membered saturated or 5, 6 or 7-membered unsaturated cyclicsystem whereby the 5, 6 or 7-membered saturated or unsaturated cyclicsystem may contain 1 to 3 heteroatoms selected from N, O or S; saidcyclic systems being optionally substituted with R¹⁵⁰; L is C₁₋₆alkyl,(C₃₋₆)cycloalkyl, C₁₋₆alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,(C₁₋₆alkyl)aryl, Het, (C₁₋₆)alkyl-Het, all of which being optionallysubstituted with R⁶⁰; or Y⁰ and L are covalently bonded to form a 5, 6,7 or 8-membered mono- or a 8, 9, 10 or 11 -membered bicyclic group whichmay be unsaturated or aromatic and which may contain 1, 2 or 3heteroatoms selected from N, O and S, wherein the mono- or bicyclicgroup is optionally substituted with R⁶⁰; or if Y⁰ is CR¹²R¹³, then Lmay also be H; or if Y⁰ is O, then L may also be OR^(C), wherein R^(C)is optionally substituted with R⁶⁰; or if Y⁰ is O, S or NR¹¹, then L mayalso be N(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(C), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—SO₂—R^(C), NR^(N2)—CO—R^(C), NR^(N3)—CO—N(R^(N2))R^(N1) orN(R^(N1))OR^(O); said R^(N1), including any heterocycle or heterobicycleformed by R^(N1), R^(N2) and/or R^(N3), and R^(C)and R^(O) beingoptionally substituted with R⁶⁰; or if Y⁰ is O or S, then L may also beOR^(6a) or N(R^(5a))R^(6a), wherein R^(5a) is defined as R^(N2), andwherein R^(6a) is:

or R^(6a)is:

wherein R^(7a) and R^(8a) are each independently defined as R^(O),COOR^(O) or CON(R^(N2))R^(N1), wherein said R^(O) is optionallysubstituted with R⁶⁰; or R^(7a) and R^(8a) are covalently bondedtogether to form a (C₃₋₇)cycloalkyl or a 4, 5- or 6-membered heterocyclehaving from 1 to 3 heteroatom selected from O, N, and S; and when L isN(R^(5a))R^(6a), either of R^(7a), or R^(8a) may be covalently bonded toR^(5a) to form a nitrogen-containing 5-or 6-membered heterocycle,wherein said cycloalkyl or heterocycle being optionally substituted byR¹⁵⁰; and W¹ is selected from a) a single bond; b) —CH₂—; c) —CH₂—CH₂—;and d) —CH═CH—; wherein the alkylene and alkenylene groups according tob), c) and d) may be substituted with (C₁₋₃) alkyl; Y²is O or S; R^(9a)is defined as R^(O), wherein said R^(O) is optionally substituted withR⁶⁰; or R^(9a) is covalently bonded to either of R^(7a) or R^(8a) toform a 5- or 6-membered heterocycle; Q¹ is aryl, Het, (C₁₋₆)alkyl-aryl,(C₁₋₆)alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all ofwhich being optionally substituted with R⁶⁰; Y¹ is O, S or NR¹⁴, whereinR¹⁴ is H or (C₁₋₆) alkyl; Z is defined as a) OR^(O); b) SO₂R^(C); c)N(R^(N2))R^(N1); d) NR^(N3)—N(R^(N2))R^(N1); e)NR^(N3)—NR^(N2)—CO—R^(C); f) NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1); g)NR^(N2)—SO₂—R^(C) or h) NR^(N3)—SO₂—N(R^(N2))R^(N1); i)NR^(N2)—CO—R^(C); j) COOR^(O); k) N(R^(N1))OR^(O); wherein R^(O) andR^(C) are optionally substituted with R⁶⁰; and said R^(N1), includingany heterocycle or heterobicycle formed by R^(N1), R^(N2), and/orR^(N3), being optionally substituted with R⁶⁰; or Z is OR^(6b) orN(R^(5b))R^(6b) wherein R^(5b)is defined as R^(N2) and R^(6b) is:

or R^(6b) is:

wherein R^(7b), R^(8b), Y³, R^(9b), W² are defined as R^(7a), R^(8a),Y², R^(9a), W¹ respectively; and Q² is aryl, Het, (C₁₋₆) alkyl-aryl,(C₁₋₆) alkyl-Het, (C₁₋₆) alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, allof which being optionally substituted with R⁶⁰ or Q² is R¹⁶⁰ or Q² isselected from the group consisting of O—C₁₋₄alkyl, S—C₁₋₄-alkyl,C₁₋₄-alkyl, C₂₋₄-alkenyl and C₂₋₄-alkynyl, all of which being optionallysubstituted with R¹⁶⁰; and R² is selected from: halogen or R²¹, whereinR²¹ is aryl or Het, said R²¹ is optionally substituted with R¹⁵⁰; R³ isselected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl,(C₁₋₃)alkyl-(C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl,(C₁₋₃)alkyl-(C₆₋₁₀)bicycloalkyl, (C₆₋₁₀)bicycloalkenyl,(C₁₋₃)alkyl-(C₆₋₁₀)bicycloalkenyl, HCy or (C₁₋₃)alkyl-HCy, wherein HCyis a saturated or unsaturated 4 to 7-membered heterocyclic group with 1to 3 heteroatoms selected from O, S and N; said alkyl, cycloalkyl,cycloalkenyl, bicycloalkyl, bicycloalkenyl, HCy and alkyl-HCy beingoptionally substituted with from 1 to 4 substituents selected from: a)halogen; b) (C₁₋₆)alkyl optionally substituted with: 1 to 3 substituentsselected from halogen; OR³¹ or SR³¹ wherein R³¹ is H, (C₁₋₆alkyl),(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or N(R³²)₂ whereineach R³² is independently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³² are covalently bonded togetherand to the nitrogen to which they are attached to form a 5, 6 or7-membered saturated heterocycle; c) OR³³ or SR³³ wherein R³³ is H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; d)N(R³⁵)₂ wherein each R³⁵ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³⁵ arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle; R^(4a),R^(4b), R⁵ each are independently H or defined as R¹⁵⁰; R⁶⁰ is eachdefined as 1 to 4 substituents independently selected from: 1 to 3substituents selected from halogen; one of each substituent selectedfrom: OPO₃H, NO₂, cyano, azido, C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl orC(═NH)NHCO(C₁₋₆)alkyl, SO₃H; and 1to 3 substituents selected from: a)(C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyl optionallycontaining 1 or 2 heteroatoms selected from N, O and S; (C₂₋₆)alkenyl,(C₂₋₈)alkynyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, all of which optionallybeing substituted with R¹⁵⁰; b) OR^(O); c) OC(O)R^(O); d) SR^(O),SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C),CONR^(N3)SO₂N(R^(N2))R^(N1), or CONR^(N2)SO₂R^(C); e) N(R^(N2))R^(N1),N(R^(N2))COOR^(C), N(R^(N2))SO₂R^(C) or N(R^(N1))R^(O); f)N(R^(2N))COR^(C); g) N(R^(N3))CON(R^(N2))R^(N1); h) N(R^(N3))COCOR^(C),N(R^(N3))COCOOR^(O) or N(R^(N3))COCON(R^(N2))R^(N1); i) COR^(O); j)COOR^(O); k) CON(R^(N2))R^(N1); l) aryl, Het, (C₁₋₄alkyl)aryl or(C₁₋₄alkyl)Het, all of which optionally being substituted with R¹⁵⁰;wherein said R^(N1), R^(C) and R^(O) are each independently optionallysubstituted with R¹⁵⁰ as defined, R¹⁵⁰ is each defined as 1 to 4substituents independently selected from: 1 to 3 substituents selectedfrom halogen; one of each substituent selected from: OPO₃H, NO₂, cyano,azido, C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl or C(=NH)NHCO(C₁₋₆)alkyl; and 1 to3 substituents selected from: a) (C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇spirocycloalkyl optionally containing 1 or 2 heteroatoms selected fromN, O and S; (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl,all of which optionally substituted with R¹⁶⁰; b) OR^(O); c) OC(O)R^(O);d) SR^(O), SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C) orCON(R^(N2)) SO₂R^(C); e) N(R^(N2))R^(N1), N(R^(N2))COOR^(C),N(R^(N2))SO₂R^(C), or N(R^(N1))R^(O); f) N(R^(N2))COR^(C); g)N(R^(N3))CON(R^(N2))R^(N1); h) N(R^(N3))COCOR^(C), N(R^(N3))COCOOR^(O),N(R^(N3))COCON(R^(N2))OH, N(R^(N3))COCON(R^(N2))OC₁₋₄-alkyl orN(R^(N3))COCON(R^(N2))R^(N1); i) COR^(O); j) COOR^(O); k) tetrazole,triazole, CONR^(N3)—SO₂N(R^(N2))R^(N1); or CON(R^(N2))R^(N1); whereinsaid R^(N1), R^(C) and/or R^(O) are optionally substituted with R¹⁶⁰ asdefined; R¹⁶⁰ is each defined as 1, 2 or 3 substituents independentlyselected from: 1, 2 or 3 fluorine substituents; and one of eachsubstituent selected from tetrazole, triazole, chlorine, bromine,iodine, CN, nitro, C₁₋₄alkyl, CF₃, COOR¹⁶¹, SO₃H, SR¹⁶¹, SCF₃, SO₂R¹⁶³,OR¹⁶¹, OCF₃, N(R¹⁶²)₂, SO₂N(R¹⁶²)₂, NR¹⁶²SO₂R^(C),NR¹⁶²COR¹⁶²CON(R¹⁶²)₂, —NR¹⁶¹—CO—COOR¹⁶¹, —NR¹⁶¹—CO—CO(NR¹⁶²)₂,—CONR¹⁶¹SO₂R^(C), CONR¹⁶¹—SO₂N(R¹⁶²)₂ or —SO₂—NR¹⁶¹—COR^(C), whereinR¹⁶¹, R¹⁶³and each R¹⁶² is independently (C₁₋₄)alkyl, (C₃₋₇)cycloalkylor (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; and R¹⁶¹ and each R¹⁶² may eachindependently also be H; or both R¹⁶² are covalently bonded together andto the nitrogen to which they are attached to form a 5, 6 or 7-memberedsaturated heterocycle; R^(O), R^(C) are independently defined as(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, aryl, Het, (C₁₋₄)alkyl-aryl and (C₁₋₄)alkyl-Het; andR^(O) may also be H; R^(N1) is independently selected from H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, aryl, Het, (C₁₋₄)alkyl-aryl, (C₁₋₄)alkyl-Het; or R^(N2),R^(N3), R^(N4) are independently H, CH₃, (C₂₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₁₋₄) alkyl-(C₃6)cycloalkyl; wherein said alkyl, cycloalkyl oralkylcycloalkyl is optionally substituted with hydroxy, halogen,carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkyl, C₁₋₆alkoxy, amino,—NH(C₁₋₄-alkyl) and/or —N(C₁₋₆-alkyl)₂; and wherein said CH₃ isoptionally substituted with halogen, carboxy or C₁₋₆-alkoxycarbonyl; andin the case a) of a group N(R^(N2))R^(N1) the substituents R^(N2) andR^(N1); or b) of a group NR^(N3)—N(R^(N2))R^(N1) the substituents R^(N3)and R^(N1), or R^(N2) and R^(N1); may be covalently bonded together toform a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containingheterocycle or a 8-, 9-, 10- or 11-membered N-containing heterobicycleeach may have additionally from 1 to 3 heteroatoms selected from O, N,and S; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, or a 8-, 9-, 10- or11-membered heterobicycle having 1 to 5 heteroatoms selected from O, Nand S; or a salt thereof.
 2. The compound according to claim 1 wherein:either A or B is N and the other B or A is C, wherein - - - between twoC-atoms represents a double bond and - - - between a C-atom and a N-atomrepresents a single bond, the group —C(═Y¹)-Z is covalently linked toeither M² or M³, M¹ is CR^(4a), M² or M³ is CR⁵, M⁴ is CR^(4b), and inaddition one or two of the groups selected from M¹, M², M³ and M⁴ mayalso be N, with the proviso that the group M² or M³ to which —C(═Y¹)-Zis linked is an C-atom, Sp is a spacer group selected from—(CR⁵¹R⁵²)_(k1)-, wherein k1 is 1, 2 or 3; R⁵¹, R⁵² are independently H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, or R⁵¹and R⁵² are covalently bonded together and to the carbon-atom to whichthey are attached to form a (C₃₋₆)cycloalkyl group, said alkyl,cycloalkyls or alkyl-cycloalkyl being optionally substituted by halogen,hydroxy, (C₁₋₆)alkoxy, cyano, amino, —NH(C₁₋₄-alkyl) and/or—N(C₁₋₄-alkyl)₂; Y^(O) is O, S, NR¹¹ or CR¹²R¹³, wherein R¹¹, R¹², R¹³are each independently defined as R^(O); R¹³ may also be COOR^(O) orSO₂R^(C); wherein R^(C) and each R^(O) is optionally substituted withR¹⁵⁰; or both R¹² and R¹³ are covalently bonded together and to thecarbon-atom to which they are attached to form a 3, 4, 5, 6 or7-membered saturated or 5, 6 or 7-membered unsaturated cyclic systemwhereby the 5, 6 or 7-membered saturated or unsaturated cyclic systemmay contain 1 to 3 heteroatoms selected from N, O or S; said cyclicsystems being optionally substituted with R¹⁵⁰; L is C₁₋₆alkyl,(C₃₋₆)cycloalkyl, C₁₋₆alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,(C₁₋₆alkyl)aryl, Het, (C₁₋₆)alkyl-Het, all of which being optionallysubstituted with R⁶⁰; or if Y⁰ is CR¹²R¹³, then L may also be H; or ifY⁰ is O, then L may also be OR^(C), wherein R^(C) is optionallysubstituted with R⁶⁰; or if Y⁰ is O, S or NR¹¹, then L may also beN(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1), NR^(N3) —NR^(N2)—CO—R^(C),NR^(N4)—NR^(N3) —CO—N(R^(N2))R^(N1), NR^(N2)—SO₂—R^(C),NR^(N2)—CO—R^(C), NR^(N3)—CO—N(R^(N2))R^(N1) or N(R^(N1))OR^(O); saidR^(N1), including any heterocycle or heterobicycle formed by R^(N1),R^(N2) and/or R^(N3), and R^(C) and R^(O) being optionally substitutedwith R⁶⁰; or if Y⁰ is O or S, then L may also be OR^(6a) orN(R^(5a))R^(6a), wherein R^(5a) is defined as R^(N2) and wherein R^(6a),is:

wherein R^(7a) and R^(8a) are each independently defined as R^(O),wherein said R^(O) is optionally substituted with R⁶⁰; or R^(7a) andR^(8a) are covalently bonded together to form a (C₃₋₇)cycloalkyl or a 4,5- or 6-membered heterocycle having from 1 to 3 heteroatom selected fromO, N, and S; and when L is N(R^(5a))R^(6a), either of R^(7a) or R^(8a)may be covalently bonded to R^(5a) to form a nitrogen-containing 5-or6-membered heterocycle, wherein said cycloalkyl or heterocycle beingoptionally substituted by R¹⁵⁰; and Y² is O or S; R^(9a) is defined asR^(O), wherein said R^(O) is optionally substituted with R⁶⁰; or R^(9a)is covalently bonded to either of R^(7a) or R^(8a) to form a 5- or6-membered heterocycle; Q¹ is aryl, Het, (C₁₋₆)alkyl-aryl,(C₁₋₆)alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all ofwhich being optionally substituted with R^(60;) Y¹ is O, S or NR¹⁴,wherein R¹⁴ is H or (C₁₋₆)alkyl; Z is defined as a) OR^(O); b) SO₂R^(C);c) N(R^(N2))R^(N1); d) NR^(N3)—N(R^(N2))R^(N1); e)NR^(N3)—NR^(N2)—CO—R^(C); f) NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1); g)NR^(N2)—SO2—R^(C) or h) NR^(N2)—CO—R^(C); i) COOR^(O); j)N(R^(N1))OR^(O); wherein R^(O) and R^(C) are optionally substituted withR⁶⁰; and said R^(N1), including any heterocycle or heterobicycle formedby R^(N1), R^(N2), and/or R^(N3), being optionally substituted with R⁶⁰;or Z is OR^(6b) or N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2)and R^(6b)is:

wherein R^(7b), R^(8b), Y³, R^(9b), Q², are defined as R^(7a), R^(8a),Y², R^(9a), Q¹, respectively; R² is selected from: halogen or R²¹,wherein R²¹ is aryl or Het, said R²¹ is optionally substituted withR¹⁵⁰; R³ is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl,(C₁₋₃)alkyl-(C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl,(C₁₋₃)alkyl-(C₆₋₁₀)bivycloalkyl, (C₆₋₁₀)bicycloalkenyl,(C₁₋₃)alkyl-(C₆₋₁₀)bicycloalkenyl, HCy or (C₁₋₃)alkyl-HCy, wherein HCyis a saturated or unsaturated 4 to 7-membered heterocyclic group with 1to 3 heteroatoms selected from O, S and N; said alkyl, cycloalkyl,cycloalkenyl, bicycloalkyl, bicycloalkenyl, HCy and alkyl-HCy beingoptionally substituted with from 1 to 4 substituents selected from: a)halogen; b) (C₁₋₆)alkyl optionally substituted with: OR³¹ or SR³¹wherein R³¹ is H, (C₁₋₆alkyl), (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or N(R³²)₂ wherein each R³² isindependently H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³² are covalently bonded togetherand to the nitrogen to which they are attached to form a 5, 6 or7-membered saturated heterocycle; c) OR³³ or SR³³ wherein R³³ is H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; d)N(R³⁵)₂ wherein each R³⁵ is independently H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; or both R³⁵ arecovalently bonded together and to the nitrogen to which they areattached to form a 5, 6 or 7-membered saturated heterocycle; R^(4a),R^(4b), R⁵ each are independently H or defined as R¹⁵⁰; R⁶⁰ is eachdefined as 1 to 4 substituents independently selected from: 1 to 3substituents selected from halogen; one of each substituent selectedfrom: OPO₃H, NO₂, cyano, azido, C(═NH)NH₂, C(═NH)NH(C₁₋₆)alkyl orC(═NH)NHCO(C₁₋₆)alkyl, SO₃H; and 1 to 3 substituents selected from: a)(C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyl optionallycontaining 1 or 2 heteroatoms selected from N, O and S; (C₂₋₆)alkenyl,(C₂₋₈)alkynyl, (C₁₋₆)alkyl-(C₃₋₇)cycloalkyl, all of which optionallybeing substituted with R¹⁵⁰; b) OR^(O); c) OC(O)R^(O); d) SR^(O),SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C) orCONR^(N2)SO₂R^(C); e) N(R^(N2))R^(N1), N(R^(N2))COOR^(C), orN(R^(N2))SO₂R^(C); f) N(R^(N2))COR^(C); g) N(R^(N3))CON(R^(N2))R^(N1);h) N(R^(N3))COCOR^(C), N(R^(N3))COCOOR^(O) orN(R^(N3))COCON(R^(N2))R^(N1); i) COR^(O); j) COOR^(O); k)CON(R^(N2))R^(N1); l) aryl, Het, (C₁₋₄alkyl)aryl or (C₁₋₄alkyl)Het, allof which optionally being substituted with R¹⁵⁰; wherein said R^(N1),R^(C) and R^(O) are each independently optionally substituted with R¹⁵⁰as defined, R¹⁵⁰ is each defined as 1 to 4 substituents independentlyselected from: 1 to 3 substituents selected from halogen; one of eachsubstituent selected from: OPO₃H, NO₂, cyano, azido, C(═NH)NH₂,C(═NH)NH(C₁₋₆)alkyl or C(═NH)NHCO(C₁₋₆)alkyl; and 1 to 3 substituentsselected from: a) (C₁₋₆) alkyl, (C₃₋₇)cycloalkyl, C₃₋₇ spirocycloalkyloptionally containing 1 or 2 heteroatoms selected from N, O and S;(C₂₋₆)alkenyl, (C₂₋₈)alkynyl, (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, all of whichoptionally substituted with R¹⁶⁰; b) OR^(O); c) OC(O)R^(O); d) SR^(O),SO₂R^(C), SO₂N(R^(N2))R^(N1), SO₂N(R^(N2))C(O)R^(C) orCON(R^(N2))SO₂R^(C); e) N(R^(N2))R^(N1), N(R^(N2))COOR^(C), orN(R^(N2))SO₂R^(C); f) N(R^(N2))COR^(C); g) N(R^(N3))CON(R^(N2))R^(N1);h) N(R^(N3))COCOR^(C), N(R^(N3))COCOOR^(O) orN(R^(N3))COCON(R^(N2))R^(N1); wherein R^(N1) is as defined or OH,O—C₄-alkyl; i) COR^(O); j) COOR^(O); k) tetrazole or CON(R^(N2))R^(N1);wherein said R^(N1), R^(C) and/or R^(O) are optionally substituted withR¹⁶⁰ as defined; R¹⁶⁰ is each defined as 1, 2 or 3 substituentsindependently selected from: 1, 2 or 3 fluorine substituents; and one ofeach substituent selected from tetrazole, chlorine, bromine, iodine, CN,nitro, C₁₋₄alkyl, CF₃, COOR¹⁶¹, SO₃H, SR¹⁶¹ SO₂R¹⁶³, OR¹⁶¹, N(R¹⁶²)₂,SO₂N(R¹⁶²)₂, SO₂NR¹⁶²COR¹⁶², NR¹⁶²SO₂R¹⁶³, NR¹⁶²COR¹⁶², or CON(R¹⁶²)₂,wherein R¹⁶¹, R¹⁶³ and each R¹⁶² is independently (C₁₋₄)alkyl,(C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; and R¹⁶¹ and each R¹⁶²may each independently also be H; or both R¹⁶² are covalently bondedtogether and to the nitrogen to which they are attached to form a 5, 6or 7-membered saturated heterocycle; R^(O), R^(C) are independentlydefined as (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, aryl, Het, (C₁₋₄)alkyl-aryl and (C₁₋₄)alkyl-Het; andR^(O) may also be H; R^(N1) is independently selected from H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, aryl, Het, (C₁₋₄)alkyl-aryl, (C₁₋₄)alkyl-Het; or R^(N2),R^(N3), R^(N4) are independently H, CH₃, (C₂₋₆alkyl), (C₃₋₆)cycloalkyl,(C₁₋₄)alkyl-(C₃₋₆)cycloalkyl; wherein said alkyl, cycloalkyl oralkylcycloalkyl is optionally substituted with hydroxy, halogen,carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, amino,—NH(C₁₋₄-alkyl) and/or —N(C₁₋₄-alkyl)₂; and wherein said CH₃ isoptionally substituted with halogen, carboxy or C₁₋₆-alkoxycarbonyl; andin the case a) of a group N(R^(N2))R^(N1) the substituents R^(N2) andR^(N1); or b) of a group NR^(N3)—N(R^(N2))R^(N1) the substituents R^(N3)and R^(N1), or R^(N2) and R^(N1); may be covalently bonded together toform a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containingheterocycle or a 8-, 9-, 10- or 11-membered N-containing heterobicycleeach may have additionally from 1 to 3 heteroatoms selected from O, N,and S; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, or a 8-, 9-, 10- or11-membered heterobicycle having 1 to 5 heteroatoms selected from O, Nand S; or a salt thereof.
 3. The compound according to claim 1 offormula (Ia)

wherein R², R³, L, M¹, M², M³, M⁴, Y¹, Y⁰, Z and Sp are as defined inclaim
 1. 4. The compound according to claim 1 of formula (Ic):

wherein A, B, R² R³, L, M¹, M³, M⁴, Y¹, Y⁰, Z and Sp are as defined inclaim
 1. 5. The compound according to claim 1 selected from the group offormulas I.1 to I.4.

wherein R², R³, R^(4a), R^(4b), R⁵ , L, Y⁰, Y¹, Z and Sp are defined asin claim
 1. 6. The compound according to claim 1, wherein Sp is a spacergroup selected from —(CR⁵¹R⁵²)_(k1)—, wherein k1 is 1, 2 or 3; and R⁵¹,R⁵² are independently H or (C₁₋₃)alkyl; and/or R⁵¹, R⁵² are covalentlybonded together and to the carbon-atom to which they are attached toform a cyclopropyl, cyclobutyl or cyclopentyl group.
 7. The compoundaccording to claim 6, wherein Sp is a spacer group selected from —CH₂—,—CH(CH₃)—, —C(CH₃)₂, —CH₂—CH₂— and


8. The compound according to claim 7, wherein Sp is —CH₂—.
 9. Thecompound according to claim 1, wherein Y⁰ is O or S.
 10. The compoundaccording to claim 1, wherein L is C₁₋₆-alkyl, (C₃₋₆)cycloalkyl,C₁₋₆alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, all of which being optionallysubstituted with R⁶⁰; or if Y⁰ is CR¹²R¹³, then L may also be H; or ifY⁰ is O, then L may also be OR^(C), wherein R^(C) is optionallysubstituted with R⁶⁰; wherein R¹², R¹³, R⁶⁰ and R^(C) are defined as inclaim
 1. 11. The compound according to claim 1, wherein Y⁰ is O, S orNR¹¹ and L is N(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(C), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—SO₂—R^(C), or N(R^(N1))OR^(O), said R^(N1), including anyheterocycle or heterobicycle formed by R^(N1), R^(N2) and/or R^(N3), andR^(C) being optionally substituted with R⁶⁰; or L is N(R^(5a))R^(6a)wherein R^(5a) is defined as R^(N2) and R^(6a) is:

or R^(6a)is:

wherein R^(7a) and R^(8a) are each independently defined as R^(O),wherein said R^(O) is optionally substituted with R⁶⁰; or R^(7a) andR^(8a)are covalently bonded together to form a second (C₃₋₇)cycloalkylor a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatomselected from O, N, and S; and either of R^(7a) or R^(8a) may becovalently bonded to R^(5a) to form a nitrogen-containing 5-or6-membered heterocycle, wherein said cycloalkyl or heterocycle beingoptionally substituted by R¹⁵⁰; and W¹ is selected from a) a singlebond; b) —CH₂—; c) —CH₂—CH₂—; and d) —CH═CH—; Y² is O or S; R^(9a) isdefined as R^(O), wherein said R^(O) is optionally substituted with R⁶⁰;or R^(9a) is covalently bonded to either of R^(7a) or R^(8a) to form a5- or 6-membered heterocycle; Q¹ is aryl, Het, (C₁₋₆)alkyl-aryl,(C₁₋₆)alkyl-Het, (C₁₋₆)alkyl-CONH-aryl or (C₁₋₆) alkyl-CONH-Het, all ofwhich being optionally substituted with R⁶⁰; wherein R¹¹, R⁶⁰, R^(O),R^(C), R^(N1), R^(N2), R^(N3), R^(N4), and H tare defined as in claim 1.12. The compound according to claim 1, wherein Y¹ is O.
 13. The compoundaccording to claim 1, wherein Z is defined as a) OR^(O); c)N(R^(N2))R^(N1); g) NR^(N2)—SO₂—R^(C); h) NR^(N3)—SO2—N(RN²)R^(N1); ori) NR^(N2)—CO—R^(C); wherein R^(O) and R^(C) are optionally substitutedwith R⁶⁰; and said R^(N1), including any heterocycle or heterobicycleformed by R^(N1) and R^(N2) being optionally substituted with R⁶⁰; or Zis OR^(6b) or N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) andR^(6b) is:

or R^(6b) is:

wherein R^(7b), R^(8b), Y³, R^(9b), W², Q², R⁶⁰, R^(O), R^(C), R^(N1),R^(N2) and R^(N3) are defined as in claim
 1. 14. The compound accordingto claim 1, wherein Sp is a spacer group selected from —CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH₂—CH₂— and

and Y⁰ is O or S; L is N(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(C), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—SO₂—R^(C) or N(R^(N1))OR^(O); said R^(N1), including anyheterocycle or heterobicycle formed by R^(N1), R^(N2) and/or R^(N3), andR^(C) being optionally substituted with R⁶⁰; or L is N(R^(5a))R^(6a)wherein R^(5a) is defined as R^(N2) and R^(6a) is:

or R⁶a is:

Y¹ is O or S; Z is defined as a) OR^(O); c) N(R^(N2))R^(N1); or g)NR^(N2)—SO₂—R^(C); wherein R^(O) and R^(C) are optionally substitutedwith R⁶⁰; and said R^(N1), including any heterocycle or heterobicycleformed by R^(N1) and R^(N2), being optionally substituted with R⁶⁰; or Zis N(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) and R^(6b) is:

or R^(6b) is:

wherein R², R³, R^(4a), R^(4b), R⁵, R^(7a), R^(8a), R^(7b), R^(8b),R^(9a), R^(9b), R⁶⁰, R^(O), R^(C), R^(N1), R^(N2), R^(N3), R^(N4), Q¹,Q², W¹, W², Y² and Y³ are defined as in claim
 1. 15. The compoundaccording to claim 14 of the formula I.1a

wherein R^(N1), including any heterocycle formed by R^(N1) and R^(N2),is optionally substituted with R⁶⁰; Z is defined as a) OR^(O); c)N(R^(N2))R^(N1); or g) NR^(N2)—SO₂—R^(C); wherein R^(O) and R^(C) areoptionally substituted with R⁶⁰; and said R^(N1), including anyheterocycle or heterobicycle formed by R^(N1) and R^(N2), beingoptionally substituted with R⁶⁰; or Z is N(R^(5b))R^(6b) wherein R^(5b)is defined as R^(N2) and R^(6b) is:

or R^(6b)is:

wherein R², R³, R^(4a), R^(4b), R⁵, R^(7b), R^(8b), R^(9b), R⁶⁰, R^(O),R^(C), R^(N1), R^(N2), R^(N3), R^(N4), Q², W² and Y³ are defined as inclaim
 14. 16. The compound according to claim 14 of the formula I.1b

wherein R^(5a) is defined as R^(N2); and R^(6a) is defined as:

or R^(6a)is:

Z is defined as a) OR^(O); c) N(R^(N2))R^(N1); or g) NR^(N2)—SO₂—R^(C);wherein R^(O) and R^(C) is optionally substituted with R⁶⁰; and saidR^(N1), including any heterocycle or heterobicycle formed by R^(N1) andR^(N2), being optionally substituted with R⁶⁰; or Z is N(R^(5b))R^(6b)wherein R^(5b) is defined as R^(N2) and R^(6b) is:

or R^(6b) is:

wherein R², R³, R^(4a), R^(4b), R⁵, R^(7a), R^(8a), R^(7b), R^(8b),R^(9a), R^(9b), R⁶⁰, R^(O), R^(C), R^(N1), R^(N2), R^(N3), R^(N4), Q¹,Q², W¹, W², Y² and Y³ are defined as in claim
 14. 17. The compoundaccording to claim 14 of the formula I.1c

wherein R^(C) is optionally substituted with R⁶⁰; Z is defined as a)OR^(O); c) N(R^(N2))R^(N1); or g) NR^(N2)—SO₂—R^(C); wherein R^(O) andR^(C) are optionally substituted with R⁶⁰; and said R^(N1), includingany heterocycle or heterobicycle formed by R^(N1) and R^(N2), beingoptionally substituted with R⁶⁰; or Z is N(R^(5b))R^(6b) wherein R^(5b)is defined as R^(N2) and R^(6b) is:

or R^(6b) is:

wherein R², R³, R^(4a), R^(4b), R⁵, R^(7b), R^(8b), R^(9b), R⁶⁰, R^(O),R^(C), R^(N1), R^(N2), R^(N3), R^(N4), Q²; W² and Y³ are defined as inclaim
 14. 18. The compound according to claim 1 of the formula I.1d

wherein L is selected from OR^(C), NR^(N3) —N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(C), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—CO—R^(C), NR^(N3)—CO—N(R^(N2))R^(N1) or N(R^(N1))OR^(O); saidR^(N1), including any heterocycle or heterobicycle formed by R^(N1),R^(N2) and/or R^(N3), and R^(C) being optionally substituted with R⁶⁰; Zis defined as a) OR^(O); c) N(R^(N2))R^(N1); or g) NR^(N2)—SO₂—R^(C);wherein R^(O) and R^(C) are optionally substituted with R⁶⁰; and saidR^(N1), including any heterocycle or heterobicycle formed by R^(N1) andR^(N2), being optionally substituted with R⁶⁰; or Z is N(R^(5b))R^(6b)wherein R^(5b) is defined as R^(N2) and R^(6b) is:

or R^(6b) is:

wherein R², R³, R^(4a), R^(4b), R⁵, R^(7b), R^(8b), R^(9b), R⁶⁰, R^(O),R^(C), R^(N1), R^(N2) , R^(N3), R^(N4), Q², W² and Y³ are defined as inclaim
 1. 19. The compound according to claim 11, wherein Y⁰ is O, S orNR¹¹, and L is N(R^(N2))R^(N1), NR^(N3)—N(R^(N2))R^(N1),NR^(N3)—NR^(N2)—CO—R^(C), NR^(N4)—NR^(N3)—CO—N(R^(N2))R^(N1),NR^(N2)—SO₂—R^(C) or N(R^(N1))OR^(O), wherein R^(N2), R^(N3), R^(N4) areeach independently H, methyl, (C₂₋₄)alkyl, (C₃₋₆)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all of which being optionally substitutedwith halogen, carboxy or (C₁₋₄)alkoxcarbonyl; and/or wherein said alkyl,cycloalkyl or alkyl-cycloalkyl is optionally substituted with hydroxy,C₁₋₃-alkyl, amino, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂ and/or—O—(C₁₋₄-alkyl); R^(N1) is H, methyl, (C₂₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-phenyl, phenyl, Het or(C₁₋₄)alkyl-Het; wherein all of said methyl, alkyl, and cycloalkylgroups are optionally substituted with C₁₋₃-alkyl, halogen, carboxy or(C₁₋₄)alkoxcarbonyl, CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂; and/orwherein all of said alkyl, and cycloalkyl, is optionally substitutedwith hydroxy, amino, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂ and/or—O—(C₁₋₄-alkyl); and in the case a) of a group N(R^(N2))R^(N1) thesubstituents R^(N1) and R^(N2) or b) of a group NR^(N3)—N(R^(N2))R^(N1)the substituents R^(N1) and R^(N3) or R^(N1) and R^(N2) may becovalently bonded together to form a 5-, 6- or 7-membered saturated orunsaturated heterocycle which may have additionally 1 or 2 heteroatomsor a 8-, 9-, 10- or 11-membered saturated or unsaturated heterobicyclewhich may have additionally from 1, 2 or 3 heteroatoms, whereby theheteroatoms are selected from O, N, and S; and wherein Het is a 4-, 5-,6- or 7-membered monocyclic group which contains 1 or 2 heteroatomsselected from N, O and S, wherein a benzene ring may be fused to themonocyclic group; and wherein said phenyl group, heterocycle,heterobicycle or Het is optionally substituted by 1 to 4 substituentsindependently selected from: 1 to 3 substituents selected from halogen;one of each substituent selected from: NO₂, cyano, azido; and 1 to 3substituents selected from: (C₁₋₄)alkyl, hydroxy, O—(C₁₋₄)alkyl, amino,—COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂,—NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, N-pyrrolidinyl, N-piperidinyl,N-morpholinyl, N-thiomorpholinyl, N-piperazinyl, —(C₁₋₄)alkyl-OH,—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,—(C₁₋₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂, wherein the alkyl-groups may be substitutedwith halogen; and wherein the N-piperazinyl-group may be N-substitutedwith C₁₋₄-alkyl; and wherein R^(O), R^(C), and R¹¹ are defined as inclaim
 11. 20. The compound according to claim 19, wherein Y₀ is O, S orNR¹¹ and L is N(R^(N2))R^(N1) wherein R^(N2) is H, methyl, (C₂₋₄)alkyl,(C₃₋₆)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all of which beingoptionally substituted with halogen, carboxy or (C₁₋₄)alkoxcarbonyl;and/or wherein said alkyl, cycloalkyl or alkyl-cycloalkyl is optionallysubstituted with hydroxy, C₁₋₃-alkyl, amino, —NH(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)₂ and/or —O—(C₁₋₄-alkyl); R^(N1) is methyl, (C₂₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, (C₁₋₄)alkyl-phenyl, Hetand (C₁₋₄)alkyl-Het; wherein the methyl, and alkyl groups are optionallysubstituted with C₁₋₃-alkyl,halogen, carboxy or (C₁₋₄)alkoxcarbonyl,CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂; and/or wherein said alkyl isoptionally substituted with hydroxy, amino, —NH(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)₂ and/or —O—(C₁₋₄-alkyl); and wherein Het is a saturatedor unsaturated 4-, 5-, 6- or 7-membered monocyclic group which contains1 or 2 heteroatoms selected from N, O and S, wherein a benzene ring maybe fused to the monocyclic group; and wherein said phenyl group,heterocycle, heterobicycle or Het is optionally substituted by 1 to 4substituents independently selected from: 1 to 3 substituents selectedfrom halogen; one of each substituent selected from: NO₂, cyano, azido;and 1 to 3 substituents selected from: (C₁₋₄)alkyl, hydroxy,O—(C₁₋₄)alkyl, amino, —COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl),CON(C₁₋₄-alkyl)₂, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, N-pyrrolidinyl,N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, N-piperazinyl,—(C₁₋₄)alkyl-OH, —(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,—(C₁₋₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂, wherein the alkyl-groups may be substitutedwith halogen; and wherein the N-piperazinyl-group may be N-substitutedwith C₁₄-alkyl; and wherein R¹¹ is defined as in claim
 19. 21. Thecompound according to claim 1, wherein Y⁰ is O, S or NR¹¹, and L isN(R^(N2))R^(N1) wherein R^(N2) and R^(N1) are covalently bonded togetherto form a heterocycle selected from azetidine, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, homopiperidine andhomopiperazine; wherein said piperazine and homopiperazine may beN-substituted with C₁₋₄alkyl, (C₃₋₆)cycloalkyl orC₁₋₄alkyl-(C₃₋₆)cycloalkyl; and wherein said heterocycles are optionallymonosubstituted by (C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, HCyor C₁₋₃alkyl-HCy, wherein HCy is selected from azetidine, pyrrolidine,piperidine, piperazine, morpholine, thiomorpholine, homopiperidine andhomopiperazine; and wherein said heterocycles, including an optionalalkyl-, cycloalkyl- or alkylcycloalkyl-group and/or HCy or C₁₋₃alkyl-HCygroup, are optionally substituted by 1 to 4 substituents independentlyselected from: 1 to 3 substituents selected from halogen and(C₁₋₄)alkyl; one of each substituent selected from: NO₂, cyano, azido;and 1 or 2 substituents selected from: hydroxy, O—(C₁₋₄)alkyl, amino,—COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂,—NH(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)₂, —(C₁₋₄)alkyl-OH,—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,—(C₁₋₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂; wherein said alkyl-groups may besubstituted with halogen.
 22. The compound according to claim 1, whereinY⁰ is O and L is OR^(6a), or wherein Y⁰ is O or S and L isN(R^(N2))R^(6a), and R^(6a) are defined as:

wherein R^(7a) is defined as H, COOH, CONH₂, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₄)alkyl-aryl, (C₁₋₄)alkyl-Het; all of which are optionallysubstituted with R⁶⁰; and R^(8a) is H or (C₁₋₄)alkyl; or R^(7a) andR^(8a) are covalently bonded together to form a second (C₃₋₇)cycloalkylor a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatomselected from O, N, and S; and when L is N(R^(5a))R^(6a), either ofR^(7a)or R^(8a)may be covalently bonded to R^(5a)to form anitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkylor heterocycle being optionally substituted by R¹⁵⁰; and W¹ is selectedfrom a) a single bond; b) —CH₂—; c) —CH₂—CH₂—; and d) —CH═CH—; whereinthe alkylene and alkenylene groups according to b), c) and d) may besubstituted with (C₁₋₃)alkyl; Q¹ is a group of the subformula IIIa

wherein Q^(1a) is aryl, Hetaryl, (C₁₋₃) alkyl-aryl or(C₁₋₃)alkyl-Hetaryl; Q^(1b) is phenyl or Hetaryl; Q^(1c) is a bond,O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynl; andR^(1q) is selected from is selected from H, CN, COOR¹⁶¹, CON(R¹⁶²)₂,SO₂N(R¹⁶²)₂ ,—N(R¹⁶²)₂, OR¹⁶¹ SR¹⁶¹, —NHCOR¹⁶², —NH—CO—COOR¹⁶¹,—NH—CO—CON(R¹⁶²)₂, NHSO₂R^(C), CONHSO₂R^(C), SO₂NHCOR^(C), tetrazole,triazole and CONHSO₂N(R¹⁶²)₂;; q is 0 or 1; wherein each aryl, phenyl,Hetaryl, alkyl, alkenyl and/or alkynyl-groups is optionally substitutedwith R¹⁶⁰; and wherein Hetaryl is an aromatic 5- or 6-memberedheterocycle having 1 or 2 heteroatoms selected from O, N, and S, or a 9-or 10-membered aromatic heterobicycle having 1 to 4 heteroatoms selectedfrom O, N, and S; and wherein R^(O), R^(C), R^(N2), R¹⁵⁰, R¹⁶⁰, R¹⁶¹ andR¹⁶² are defined as in claim
 1. 23. The compound according to claim 1,wherein Y⁰ is O and L is OR^(6a), or wherein Y⁰ is O or S and L isN(R^(5a))R^(6a), wherein R^(5a) is defined as R^(N2); and R^(6a) isdefined as:

wherein R^(7a) and R^(8a) are each independently defined as R^(O),wherein said R^(O) is optionally substituted with R⁶⁰; or R^(7a) andR^(8a) are covalently bonded together to form a second (C₃₋₇)cycloalkylor a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatomselected from O, N, and S; and when L is N(R^(5a))R^(6a), either ofR^(7a) or R^(8a) may be covalently bonded to R^(5a) to form anitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkylor heterocycle being optionally substituted by R¹⁵⁰; and Y² is O or S;R^(9a) is defined as R^(O), wherein said R^(O) is optionally substitutedwith R⁶⁰; or R^(9a) is covalently bonded to either of R^(7a), or R^(8a)to form a 5- or 6-membered heterocycle; Q¹ is a group of the subformulaIIIa

wherein Q^(1a) is aryl, Hetaryl, (C₁₋₃) alkyl-aryl or(C₁₋₃)alkyl-Hetaryl; Q^(1b) is phenyl or Hetaryl; Q^(1c) is a bond,O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl;and R^(1q) is selected from H, CN, COOR¹⁶¹, CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂,—N(R¹⁶²)₂, OR¹⁶¹, SR¹⁶¹, —NHCOR¹⁶², —NH—CO—COOR¹⁶¹, —NH—CO—CON(R¹⁶²)₂,NHSO₂R^(C), CONHSO₂R^(C), SO₂NHCOR^(C), tetrazole, triazole andCONHSO₂N(R¹⁶²)₂;; q is 0 or 1; wherein each aryl, phenyl, Hetaryl,alkyl, alkenyl and/or alkynyl-groups is optionally substituted withR¹⁶⁰; and wherein Hetaryl is an aromatic 5- or 6-membered heterocyclehaving 1 or 2 heteroatoms selected from O, N, and S, or a 9- or10-membered aromatic heterobicycle having 1 to 4 heteroatoms selectedfrom O, N, and S; and wherein R^(O), R^(C), R^(N2) R¹⁵⁰ R¹⁶⁰ R¹⁶¹ andR¹⁶² are defined as in claim
 1. 24. The compound according to claim 22or 23, wherein a) Q^(1a) is phenyl, q is 1 and Q^(1c) is a bond; b)Q^(1a) is phenyl, q is 0 and Q^(1c) is vinyl; or c) Q^(1a) is a 9- or10-membered aromatic heterobicycle having 1 or 2 heteroatoms selectedfrom O, N, and S, said heterobicycle optionally being substituted withR¹⁶⁰; q is 0 and Q^(1c) is a bond, —CH₂—CH₂— or —CH═CH—.
 25. Thecompound according to claim 22 or 23, wherein the group Q^(1c)—R^(1q) is—CH═CH—COOH.
 26. The compound according to claim 13, wherein Z isdefined as OR^(O), wherein R^(O) is optionally substituted with R⁶⁰; andwherein R^(O) and R⁶⁰ are defined as in claim
 13. 27. The compoundaccording to claim 26, wherein Z is OR^(O) wherein R^(O) is H,C₁₋₄alkyl, (C₃₋₆)cycloalkyl, C₁₋₃alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl,(C₁₋₃alkyl)phenyl, (C₁₋₃)alkyl-pyridinyl, wherein said alkyl,alkyl-cycloalkyl, cycloalkyl, alkenyl, alkyl-phenyl, or alkyl-pyridinylis optionally substituted with 1 to 3 substituents independentlyselected from: 1, 2 or 3 fluorine substituents; and one of eachsubstituent selected from chlorine, bromine, iodine, CN, nitro,C₁₋₄alkyl, CF₃, COOR¹⁶¹, SO₂R¹⁶¹, OR¹⁶¹, N(R¹⁶²)₂, SO₂N(R¹⁶²)₂,NR¹⁶²COR¹⁶² or CON(R¹⁶²)₂, wherein R¹⁶¹ and each R¹⁶² is independentlyH, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl; orboth R¹⁶² are covalently bonded together and to the nitrogen to whichthey are attached to form a 5, 6 or 7-membered saturated heterocycle.28. The compound according to claim 27, wherein Z is OH.
 29. Thecompound according to claim 13, wherein Z is defined as N(R^(N2))R^(N1);said R^(N1), including any heterocycle or heterobicycle formed by R^(N1)and R^(N2), being optionally substituted with R⁶⁰; and wherein R⁶⁰,R^(N1) and R^(N2) are defined as in claim
 13. 30. The compound accordingto claim 29, wherein Z is defined as N(R^(N2))R^(N1) wherein R^(N2) isH, methyl, (C₂₋₄)alkyl, (C₃₋₆)cycloalkyl or(C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, all of which being optionally substitutedwith halogen, carboxy or (C₁₋₄)alkoxycarbonyl; and/or wherein saidalkyl, cycloalkyl or alkyl-cycloalkyl is optionally substituted withhydroxy, C₁₋₃-alkyl, amino, —NH(C₁₋₄-alkyl), —N(C¹⁻⁴-alkyl)₂ and/or—O—(C₁₋₄-alkyl); R^(N1) is methyl, (C₂₋₆)alkyl, (C₁₋₄)alkyl-phenyl or(C₁₋₄)alkyl-Het; wherein the methyl and alkyl groups are optionallysubstituted with C₁₋₃-alkyl, halogen, carboxy or (C₁₋₄)alkoxycarbonyl,CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂; and/or wherein said alkyl isoptionally substituted with hydroxy, amino, —NH(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)₂ and/or —O—(C₁₋₄-alkyl); and wherein Het is a 4-, 5-, 6-or 7-membered monocyclic group which contains 1 or 2 heteroatomsselected from N, O and S, wherein a benzene ring may be fused to themonocyclic group; and wherein said phenyl group, heterocycle,heterobicycle or Het is optionally substituted by 1 to 4 substituentsindependently selected from: 1 to 3 substituents selected from halogen;one of each substituent selected from: NO₂, cyano, azido; and 1 to 3substituents selected from: (C₁₋₄)alkyl, hydroxy, O—(C₁₋₄)alkyl, amino,—COOH, —COO(C₁₋₄)alkyl, CONH₂, CONH(C₁₋₄-alkyl), CON(C₁₋₄-alkyl)₂,—NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, N-pyrrolidinyl, N-piperidinyl,N-morpholinyl, N-thiomorpholinyl, N-piperazinyl, —(C₁₋₄)alkyl-OH,—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-COOH,—(C₁₋₄)alkyl-COO(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CONH₂,—(C₁₋₄)alkyl-CONH(C₁₋₄-alkyl), —(C₁₋₄)alkyl-CON(C₁₋₄-alkyl)₂,—(C₁₋₄)alkyl-amino, —(C₁₋₄)alkyl-NH(C₁₋₄-alkyl),—(C₁₋₄)alkyl-N(C₁₋₄-alkyl)₂, wherein the alkyl-groups may be substitutedwith halogen; and wherein the N-piperazinyl-group may be N-substitutedwith (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl. 31.The compound according to claim 30, wherein Z is defined asN(R^(N2))R^(N1) wherein R^(N2) is H, methyl, ethyl, n-propyl, i-propyl,all of which being optionally substituted with methyl, fluorine,chlorine, carboxyl or methoxycarbonyl; and/or wherein said ethyl,n-propyl or i-propyl is optionally substituted with hydroxy, amino,—NH(CH₃), —N(CH₃)₂ and/or —O—(CH₃); R^(N1) is methyl, ethyl, n-propyl,i-propyl, benzyl, phenylethyl, pyridinylmethyl or pyridinylethyl;wherein all of said methyl, ethyl, n-propyl, and i-propyl, groups areoptionally substituted with fluorine, chlorine, methyl, ethyl, carboxy,methoxycarbonyl, CONH₂, CONH(CH₃), CON(CH₃)₂; and/or wherein said ethyl,n-propyl or i-propyl is optionally substituted with hydroxy, amino,—NH(CH₃), —N(CH₃)₂ and/or —O—CH₃; and wherein said phenyl and pyridinylgroup is optionally substituted by 1, 2 or 3 substituents independentlyselected from: 1, 2 or 3 substituents selected from halogen; one of eachsubstituent selected from: NO₂, cyano, azido; and 1, 2 or 3 substituentsselected from: methyl, trifluoromethyl, ethyl, n-propyl, i-propyl,hydroxy, methoxy, ethoxy, —COOH, —COOCH₃, CONH₂, CONH(CH₃), CON(CH₃)₂,amino, —NH(CH₃), —N(CH₃)₂, —CH₂—OH, —CH₂—O—CH₃, —CH₂—NH₂, —CH₂—N(CH₃)₂and —(CH₂)₂—OH.
 32. The compound according to claim 1, wherein Z isNR^(N2)—SO₂—R^(C) or NR^(N2)—CO—R^(C) wherein R^(N2) is H, (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl or (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, and R^(C) is(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl,(C₂₋₆)alkenyl, phenyl, naphthyl, Het, (C₁₋₃)alkyl-phenyl,(C₁₋₃)alkyl-naphthyl, (C₁₋₃)alkyl-Het, wherein said alkyl, cycloalkyl,alkyl-cycloalkyl, alkenyl, phenyl, Het, alkyl-phenyl, alkyl-naphthyl oralkyl-Het, are all optionally substituted with 1 to 4 substituentsselected from R⁶⁰; wherein Het and R⁶⁰ are defined as in claim
 1. 33.The compound according to claim 1, wherein Z is OR^(6b) orN(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) and R^(6b) isdefined as:

wherein R^(7b) is defined as H, COOH, CONH₂, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₄)alkyl-(C₃₋₆)cycloalkyl, (C₂₋₆)alkenyl, aryl,Het, (C₁₋₄)alkyl-aryl, (C₁₋₄)alkyl-Het; all of which are optionallysubstituted with R⁶⁰; and R^(8b) is H or (C₁₋₄)alkyl; or R^(7b) andR^(8b) are covalently bonded together to form a second (C₃₋₇)cycloalkylor a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatomselected from O, N, and S; and when Z is N(R^(5b))R^(6b), either ofR^(7b) or R^(8b) may be covalently bonded to R^(5b) to form anitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkylor heterocycle being optionally substituted by R¹⁵⁰; and W² is selectedfrom a) a single bond; b) —CH₂—; c) —CH₂—CH₂—; and d) —CH═CH—; whereinthe alkylene and alkenylene groups according to b), c) and d) may besubstituted with (C₁₋₃)alkyl; Q² is a group of the subformula IIIb

wherein Q^(2a) is aryl, Hetaryl, (C₁₋₃) alkyl-aryl or(C₁₋₃)alkyl-Hetaryl; Q^(2b) is a phenyl or Hetaryl; Q^(2c) is a bond,O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl,wherein said O—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl orC₂₋₄-alkynyl are optionally substituted with R¹⁷⁰; wherein R¹⁷⁰ isdefined as H or as 1, 2 or 3 substituents independently selected from:1, 2, or 3 substituents selected from halogen; one or two of eachsubstituent selected from (C₁₋₄) alkyl, (C₁₋₄) alkoxy, (C₃₋₅)cycloalkyl, or cyano; wherein (C₁₋₄) alkyl may optionally be substitutedwith 1 to 3 halogen atoms; and R^(2q) is selected from H, CN, COOR¹⁶¹,CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂, —N(R¹⁶²)₂, OR¹⁶¹, SR¹⁶¹, —NHCOR¹⁶²,—NH—CO—COOR¹⁶¹, —NH—CO—CON(R¹⁶²)₂, NHSO₂R^(C), CONHSO₂R^(C),SO₂NHCOR^(C), tetrazole, triazole and CONHSO₂N(R¹⁶²)₂; qa is 0 or 1; qbis 0 or 1; wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/oralkynyl-groups is optionally substituted with R¹⁶⁰; and wherein Hetarylis an aromatic 5- or 6-membered heterocycle having 1 or 2 heteroatomsselected from O, N, and S, or a 9- or 10-membered aromatic heterobicyclehaving 1 to 4 heteroatoms selected from O, N, and S; and wherein Het,R^(O), R^(C), R^(N2), R⁶⁰, R¹⁵⁰, R¹⁶⁰, R¹⁶¹ and R¹⁶² are defined as inclaim
 1. 34. The compound according to claim 1, wherein Z is OR^(6b) orN(R^(5b))R^(6b) wherein R^(5b) is defined as R^(N2) and R^(6b) is:

wherein R^(7b) and R^(8b) are each independently defined as R^(O),wherein said R^(O) is optionally substituted with R⁶⁰; or R^(7b) andR^(8b) are covalently bonded together to form a (C₃₋₇)cycloalkyl or a 4,5- or 6-membered heterocycle having from 1 to 3 heteroatom selected fromO, N, and S; or when Z is N(R^(5b))R^(6b), either of R^(7b) or R^(8b)may be covalently bonded to R^(5b) to form a nitrogen-containing 5-or6-membered heterocycle, wherein said cycloalkyl or heterocycle beingoptionally substituted by R⁶⁰; and Y³ is O or S; R^(9b) is defined asR^(O), wherein said R^(O) is optionally substituted with R¹⁵⁰; or R^(9b)is covalently bonded to either of R^(7b) or R^(8b) to form a 5- or6-membered heterocycle; Q² is a group of the subformula IIIb

wherein Q^(2a) is aryl, Hetaryl, (C₁₋₃)alkyl-aryl or(C₁₋₃)alkyl-Hetaryl;Q^(2b) is a phenyl or Hetaryl; Q^(2c) is a bond, O—C₁₋₄-alkyl,S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl, wherein saidO—C₁₋₄-alkyl, S—C₁₋₄-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl areoptionally substituted with R¹⁷⁰; wherein R¹⁷⁰ is defined as H or as 1,2 or 3 substituents independently selected from: 1, 2, or 3 substituentsselected from halogen; one or two of each substituent selected from(C₁₋₄) alkyl, (C₁₋₄) alkoxy, (C₃₋₅) cycloalkyl, or cyano; wherein (C₁₋₄)alkyl may optionally be substituted with 1 to 3 halogen atoms; andR^(2q) is selected from H, CN; COOR¹⁶¹, CON(R¹⁶²)₂, SO₂N(R¹⁶²)₂,—N(R¹⁶²)₂, OR ¹⁶¹, SR¹⁶¹, —NHCOR¹⁶², —NH—CO—COOR¹⁶¹, —NH—CO—CON(R¹⁶²)₂,CONHSO₂R^(C), tetrazole, triazole and CONHSO₂N(R¹⁶²)₂; qa is 0 or 1; qbis 0 or 1; wherein each aryl, phenyl, Hetaryl, alkyl, alkenyl and/oralkynyl-groups is optionally substituted with R^(160;) and whereinHetaryl is an aromatic 5- or 6-membered heterocycle having 1 or 2heteroatoms selected from O, N, and S, or a 9- or 10-membered aromaticheterobicycle having 1 to 4 heteroatoms selected from 0, N, and S; andwherein R^(O), R^(C), R^(N2), R⁶⁰, R¹⁵⁰, R¹⁶⁰, R¹⁶¹ and R¹⁶² are definedas in claim
 1. 35. The compound according to claim 33 or 34, wherein a)qa is 1, Q^(2a) is phenyl, qb is 1 and Q^(2c) is a bond; b) qa is 1,Q^(2a) is phenyl, qb is 0 and Q^(2c) is —CH=C(R¹⁷⁰)—, wherein R¹⁷⁰ isselected from H, F, —CH₃ or —CH₂CH₃; or c) qa is 1, Q^(2a) is a 9- or10-membered aromatic heterobicycle having 1 or 2 heteroatoms selectedfrom O, N, and S, said heterobicycle optionally being substituted withR¹⁶⁰; qb is 0 and Q^(2c) is a bond, —CH₂—CH₂— or —CH═C(R¹⁷⁰)—, whereinR¹⁷⁰ is selected from H, F, —CH₃ or —CH₂CH₃.
 36. The compound accordingto claim 33 or 34, wherein the group Q^(2c)-R^(2q) is —CH═C(R¹⁷⁰)—COOH,wherein R¹⁷⁰ is selected from H, F, —CH₃ or —CH₂CH₃.
 37. The compoundaccording to claim 1, wherein R² is R²¹, wherein R²¹ is phenyl or Hetselected from the group of formulas

and wherein said R²¹ is unsubstituted or substituted with R¹⁵⁰, beingdefined as in claim
 1. 38. The compound according to claim 1, wherein R²is R²¹, wherein R²¹ is defined as in claim 1, and wherein R²¹ isoptionally substituted with 1, 2 or 3 substituents selected from: 1 to 3substituents selected from halogen; one of each substituent selectedfrom: N0₂, cyano, azido; and 1 to 2 substituents selected from: a)(C₁₋₄)alkyl or (C₁₋₄)alkoxy, both optionally substituted with OH,O(C₁₋₄)alkyl, SO₂(C₁₋₄ alkyl), 1 to 3 halogen atoms, amino, NH(CH₃) orN(CH₃)₂); b) NR¹¹¹R¹¹² wherein both R¹¹¹ and R¹¹² are independently H,(C₁₋₄)alkyl, or R¹¹² is (C₃₋₇)cycloalkyl, (C₁₋₃)alkyl(C₃₋₇)cycloalkyl,phenyl, benzyl; or both R¹¹¹ and R¹¹² are covalently bonded together andto the nitrogen to which they are attached to form a nitrogen-containingheterocycle, each of said alkyl, cycloalkyl, alkylcycloalkyl, phenyl andbenzyl, being optionally substituted with halogen or: OR^(2h) orN(R^(2h))₂, wherein each R^(2h) is independently H, (C₁₋₄)alkyl, or bothR^(2h) are covalently bonded together and to the nitrogen to which theyare attached to form a nitrogen-containing heterocycle; c) NHCOR¹¹⁷wherein R¹¹⁷ is (C₁₋₄)alkyl, O(C₁₋₄)alkyl or O(C₃₋₇)cycloalkyl; and e)CONH₂, CONH(C₁₋₄alkyl), CON(C₁₋₄alkyl)₂.
 39. The compound according toclaim 1, wherein R³ is selected from (C₃₋₇)cycloalkyl,(C₅₋₇)cycloalkenyl, (C₆₋₁₀)bicycloalkyl, (C₆-₁₀)bicycloalkenyl, or HCy,wherein said groups are unsubstituted or mono- or disubstituted byhalogen, hydroxy, C₁₋₄alkyl and/or O—C₁₋₄alkyl, wherein the alkyl groupsmay be fluorinated; wherein HCy is defined as in claim
 1. 40. Thecompound according to claim 39, wherein R³ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, or a group selected from

wherein all said groups are unsubstituted or substituted by fluorine,C₃alkyl or CF₃.
 41. The compound according to claim 40, wherein R³ iscyclopentyl or cyclohexyl.
 42. The compound according to claim 1,wherein R⁶⁰ is each defined as 1 to 4 substituents independentlyselected from: 1 to 3 substituents selected from halogen; one of eachsubstituent selected from: NO₂, cyano, azido; and 1 to 3 substituentsselected from: a) (C₁₋₄) alkyl, (C₃₋₇)cycloalkyl, (C₂₋₄)alkenyl,(C₂₋₄)alkynyl, (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, all of which optionallybeing substituted with R¹⁵⁰; b) OR^(O); e) N(R^(N2))R^(N1); f)N(R^(N2))COR^(C); j) COOR^(O); k) CON(R^(N2))R^(N1); l) phenyl, Het,(C₁₋₃alkyl)phenyl or (C₁₋₃alkyl)Het; wherein Het is selected from furan,tetrahydrofuran, thiophene, tetrahydrothiophene, tetrahydropyran,pyridinyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, homopiperidine and homopiperazine, all of whichoptionally being substituted with R¹⁵⁰; wherein said R^(N1), R^(C)and/or R^(O) are optionally substituted with R¹⁵⁰ as defined, and R¹⁵⁰,R^(N1), R^(N2), R^(C) and R^(O) are defined as in claim
 1. 43. Thecompound according to claim 1, wherein R¹⁵⁰ is defined as 1 to 4substituents independently selected from: 1 to 3 fluorine-substituents;one of each substituent selected from: chlorine, bromine, iodine, NO₂,cyano, azido; and 1 to 3 substituents selected from: a) (C₁₋₃) alkyl,CF₃, (C₃₋₆)cycloalkyl, (C₁₋₃) alkyl-(C₃₋₆)cycloalkyl, all of whichoptionally substituted with R¹⁶⁰; b) OR^(O); e) N(R^(N2))R^(N1); f)N(R^(N2))COR^(C); j) COORO; k) CON(R^(N2))R^(N1); wherein said R^(N1),R^(C) and/or R^(O) are optionally substituted with R¹⁶⁰ as defined; andR¹⁶⁰, R^(N1), R^(N2), R^(C) and R^(O) are defined as in claim
 1. 44. Thecompound according to claim 1, wherein R¹⁶⁰ is defined as 1, 2 or 3substituents independently selected from: 1, 2 or 3 fluorinesubstituents; and one of each substituent selected from chlorine,bromine, iodine, CN, nitro, methyl, trifluoromethyl, ethyl, n-propyl,i-propyl, COOH, COOCH₃, OH, OCH₃, OCF₃, NH₂, NHCH₃, N(CH₃)₂, SO₂NH₂,SO₂NHCOCH₃, NHCOCH₃ or CONH₂, CONHCH₃ and CON(CH₃)₂.
 45. The compoundaccording to claim 1, wherein R^(O) and R^(C) are each defined as(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, phenyl,benzyl, Het, (C₁₋₃)alkyl-Het; all of which are optionally substituted asdefined; and R^(O) may also be H; R^(N1) is H, (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl, (C₁₋₃)alkyl-(C₃₋₆)cycloalkyl, phenyl, benzyl,phenylethyl, Het, (C₁₋₃)alkyl-Het; wherein said alkyl, cycloalkyl,alkyl-cycloalkyl, phenyl, benzyl, phenylethyl, Het and alkyl-Het areoptionally substituted as defined; or R^(N2), R^(N3), R^(N4) areindependently H, methyl, ethyl, n-propyl, i-propyl, cyclopropyl,cyclopropylmethyl; all of which being optionally substituted withfluorine, carboxy or methoxycarbonyl; and/or wherein said ethyl,n-propyl or i-propyl is optionally substituted with hydroxy, methyl,methoxy, amino, —NH(CH₃) and/or —N(CH₃)₂; and in the case a) of a groupN(R^(N2))R^(N1) the substituents R^(N2) and R^(N1) or b) of a groupNR^(N3)—N(R^(N2))R^(N1) the substituents R^(N3) and R^(N1) or R^(N2) andR^(N1) may be covalently bonded together to form a 5-, 6- or 7-memberedsaturated heterocycle which may have additionally one heteroatomselected from O, N, and S, wherein said heterocycle is optionallysubstituted as defined; <wherein Het is defined as in claim
 1. 46. Thecompound according to claim 1 wherein R^(4a), R^(4b), R⁵ each areindependently H, hydroxy, halogen, cyano, nitro, carboxyl, (C₁₋₄)alkyl,CF₃, (C₁₋₄)alkoxy, —O—(C₃₋₇)cycloalkyl,—1O—(C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, —O-aryl, —O—(C₁₋₃)alkyl-aryl, —O-Het,—O—(C₁₋₃)alkyl-Het, NR^(N1)R^(N2), COR^(O), NR^(N2)COR^(C),CONR^(N2)R^(N1), or NR^(N3)CONR^(N1)R^(N2), wherein all said alkyl andalkoxy groups may be mono-, di- or trisubstituted with fluorine ormono-substituted with chlorine or bromine; and wherein R^(O), R^(N1),R^(N2), R^(N3), R¹⁶⁰, and Het are as defined in claim
 1. 47. Thecompound according to claim 46 wherein R^(O) and R^(N1) areindependently H, (C₁₋₄)alkyl, aryl, or (C₁₋₃)alkyl-aryl; R^(C) is(C₁₋₄)alkyl, aryl, or (C₁₋₃)alkyl-aryl; wherein all of said aryl isphenyl optionally substituted with R¹⁶⁰, wherein R¹⁶⁰ is defined as inclaim 46; and R^(N2) and R^(N3) are each H or methyl; wherein all saidalkyl groups may be mono-, di- or trisubstituted with fluorine ormono-substituted with chlorine or bromine.
 48. The compound according toclaim 46 wherein R^(4a), R^(4b), R⁵ each are independently H, hydroxy,halogen, cyano, nitro, methyl, CF₃, methoxy, carboxy, amino, —NMe₂,—CONH₂, —NHCONH₂, —CO—NHMe, —NHCONHMe, —CO—NMe₂ or —NHCONMe₂.
 49. Thecompound according to claim 48 wherein R^(4a), R^(4b), R⁵ each areindependently H, methyl or methoxy.
 50. The compound according to claim1 wherein at least two of R^(4a), R^(4b), R⁵ are H.
 51. The compoundaccording to claim 1 of the formula:

wherein R³ is C-cycloalkyl and the index n and the substituents L, R²are defined according to the following table Cpd. # R² n L 1002

6

1003

6

1004

6

1007

6

1008

6

1010

6

1012

6

1016

6

1017

6

1019

6

1020

6

1021

6

1023

6

1024

6

1025

6

1027

6

1028

6

1030

6

1031

6

1033

6

1034

6

1035

6

1037

6

1038

6

1043

5

1044

5

1045

6

1050

6

1051

6

1052

6

1053

6

1054

6

1055

6

1057

6

1058

6

1059

6

1066

6

1067

6

1068

6

1072

6

1073

6

1074

6

1075

6

1076

6

1077

6

1079

6

1080

6

1081

6

1082

6

1090

6

1092

6

1094

6

1096

6

1097

6

1098

6

1099

6

1100

6

1102

6

1103

6

1104

6

1110

6

1111

6

1112

6

1116

6

1118

6

1119

6

1120

6

1121

6

1122

6

1125

6

1126

6

1127

6

1128

6

1129

6

1130

6

1131

6

1132

6

1133

6


52. The compound according to claim 1 of the formula:

wherein the substituents R^(N2) and R^(C) are defined according to thefollowing table Cpd. # R^(N2) R^(C) 2001 H

2002 H

2003 H

2004 H

2005 H

2006 H

2007 H

2008 H

2009 H

2010 H

2011 H

2012 H

2013 H

2014 H

2015 H

2016 H

2017 H

2018 H

2019 H

2020 H

2021 H

2022 H

2024 H

2025 H

2026 H

2027 H

2028 H

2029 H

2030 H

2031 H

2033 H

2034 H

2035 H

2036 H

2037 H

2038 H

2039 H

2040 H

2041 H

2042 H

2044 H

2045 H


53. The compound according to claim 1 of the formula:

wherein R³ is C_(n)-cycloalkyl and the index n and the substituents L,R², R^(7b), R^(8b) and Q² are defined according to the following tableCpd. # R² n L

Q² 3001

5

3002

6

3003

6

3004

6

3005

6

3006

6

3007

6

3008

6

3009

6

3010

5

3011

5


54. The compound according to claim 1 of the formula:

wherein R³ is C_(n)-cycloalkyl and the index n and the substituents L,R² and Z are defined according to the following table Cpd. # R² n L Z4003

6

4004

6

4005

6

4006

6

4029

6

4030

6

4032

6

4041

6

4042

6

4043

6

4058

6

4059

6

4062

6

4067

6

4068

5

4069

6

4070

5

4072

6

4077

6

4081

6

4082

6

4083

6

4084

6

4085

6

4086

6

4087

6

4088

6

4089

6

4090

6

4092

6

4093

6

4094

6

4095

6

4096

6

4097

6

4099

6

4100

6

4102

6

4103

6

4107

6

4109

6

4110

6


55. The compound according to claim 1 chosen from one of the followingformulas: Cpd. # Formula 6002

7001

7004

7005


56. Use of a compound of the formula I according to claim 1, or apharmaceutically acceptable salt thereof, as an inhibitor of HCVpolymerase.
 57. Use of a compound of the formula I according to claim 1,or a pharmaceutically acceptable salt thereof, as an inhibitor of RNAdependent RNA polymerase activity of the enzyme NS5B, encoded by HCV.58. Use of a compound of the formula I according to claim 1, or apharmaceutically acceptable salt thereof, as an inhibitor of HCVreplication.
 59. A method of treating or preventing HCV infection in amammal, comprising administering to the mammal an effective amount of acompound of formula I according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 60. A method of treating or preventing HCVinfection in a mammal, comprising administering to the mammal aneffective amount of a compound of formula I according to claim 1, or apharmaceutically acceptable salt thereof in combination with anotherantiviral agent.
 61. A pharmaceutical composition for the treatment orprevention of HCV infection, comprising an effective amount of acompound of formula I according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 62.The composition according to claim 61 further comprising atherapeutically effective amount of one or more antiviral agents. 63.The composition according to claim 62, wherein said antiviral agent isselected from: ribavirin and amantadine.
 64. The composition accordingto claim 62 wherein the antiviral agent is an other anti-HCV agent. 65.The pharmaceutical composition according to claim 64, wherein the otheranti-HCV agent is an immunomodulatory agent, selected from α-, β-, δ-,γ-, and ω-interferon.
 66. The composition according to claim 64, whereinsaid anti-HCV agent is another inhibitor of HCV polymerase.
 67. Thecomposition according to claim 64, wherein the other anti-HCV agent isan inhibitor of HCV NS3 protease.
 68. The composition according to claim64, wherein the other anti-HCV agent is an inhibitor of another targetin the HCV life cycle.
 69. The composition according to claim 68,wherein said inhibitor of another target in the HCV life cycle is anagent that inhibits a target selected from HCV helicase, HCV NS2/3protease and HCV IRES.
 70. Use of a compound of formula I according toclaim 1, or of a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment and/or the prevention of aFlaviviridae viral infection
 71. Use of a compound of formula Iaccording to claim 1, or of a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment and/or theprevention of an HCV infection.
 72. An intermediate compound representedby the formula 2(v) and 2′(v)

wherein Y⁰, L, Sp, R^(O) and R³ are defined as in claim 1; and X is Cl,Br or I.
 73. An intermediate compound represented by the formula

wherein Y¹, Z, R², R³, R^(4a), R^(4b) and R⁵ are defined as in claim 1;not including compounds P1, P2, P3 and P4 of the following formula

wherein Cpd. R² Z P1

—O—CH3 P2

—OH P3

—OH P4

—OH


74. Use of an intermediate compound represented by the formula 2(v) and2′(v)

wherein Y⁰, L, Sp, R^(O) and R³ are defined as in claim 1, and X is Cl,Br or I; for the manufacture of a compound according to claim
 1. 75. Useof an intermediate compound represented by the formula

wherein Y¹, Z, R², R ³, R^(4a), R^(4b) and R⁵ are defined as in claim 1;not including compounds P1, P2, P3 and P4 of the following formula

wherein Cpd. R² Z P1

—O—CH3 P2

—OH P3

—OH P4

—OH

for the manufacture of a compound according to claim
 1. 76. A processfor producing compounds of formula I.1

wherein Y⁰, L, Sp, R^(O), R² and R³ are defined as in claim 1,comprising the reaction of an indole derivative of the formula 2(iv)

wherein R^(O) and R³ are defined as hereinbefore and X is Cl, Br or I;according to one of the following methods a), b), c) or d): a) 1.)cross-coupling of the indole derivative of the formula 2(iv) with i) astannane derivative of the formula R²—SnR′₃, wherein R² is defined ashereinbefore and R′ is a C₁₋₈-alkyl or aryl group; or ii) a boronic acidderivative R²—B(OH)₂ and R²—B(OR′)₂, wherein R² and R′ are defined ashereinbefore; under transition metal catalysis to yield an indolederivative of the formula 2(vii)

wherein R^(O), R² and R³ are defined as hereinbefore; 2.) the indolederivative of the formula 2(vii) is further processed by N-alkylationusing the electrophilic reagent X—Sp—C(═Y⁰)—L, wherein X is a leavinggroup selected from Cl, Br, I, mesylate, triflate, or tosylate; and Sp,Y⁰ and L are as defined hereinbefore, in the presence of a strong base,yielding the product of the formula I.1; or b) 1.) halogen-metalexchange of the indole derivative of the formula 2(iv) using analkyllithium reagent or lithium metal; and 2.) trans-metallation of thereaction product yielded by the previous step using: i) a trialkyl tinhalide; ii) a trialkyl borate; or iii) zinc chloride; and 3.)cross-coupling of the reaction product yielded by the previous stepusing R²—X, wherein R² is defined as hereinbefore and X is F, Cl, Br, Ior triflate, under transition metal catalysis to yield an indolederivative of the formula 2(vii) as defined hereinbefore; and 4.) theindole derivative of the formula 2(vii) is further processed byN-alkylation using the electrophilic reagent X—Sp—C(═Y⁰)—L, wherein X isa leaving group selected from Cl, Br, I, mesylate, triflate, ortosylate; and Sp, Y⁰ and L are as defined hereinbefore, in the presenceof a strong base, yielding the product of the formula I.1; or c) 1.)N-alkylation of the indole derivative of the formula 2(iv) using theelectrophilic reagent X—Sp—C(═Y⁰)-L, wherein X is a leaving groupselected from Cl, Br, I, mesylate, triflate, or tosylate; and Sp, Y⁰ andL are as defined hereinbefore, in the presence of a strong base,yielding the indole derivative of the formula 2(v)

2.) 1.) halogen-metal exchange of the derivative of the formula 2(v)using an alkyllithium reagent or lithium metal; and 2.)trans-metallation of the reaction product according to the previous stepusing: i) a trialkyl tin halide; ii) alkyl borate; or iii) zincchloride; and 3.) cross-coupling of the reaction product according tothe previous step using R²—X, wherein R² is defined as hereinbefore andX is F, Cl, Br, I or triflate, under transition metal catalysis yieldingthe product of the formula I.1; or d) 1.) N-alkylation of the indolederivative of the formula 2(iv) using the electrophilic reagentX—Sp—C(═Y⁰)—L, wherein X is a leaving group selected from Cl, Br, I,mesylate, triflate, or tosylate; and Sp, Y⁰ and L are as definedhereinbefore, in the presence of a strong base, yielding the indolederivative of the formula 2(v) as defined hereinbefore; and 2.)cross-coupling of the indole derivative of the formula 2(v) with i) astannane derivative of the formula R²—SnR′₃, wherein R² is defined ashereinbefore and R′ is a C₁₋₈ alkyl or aryl group; or ii) a boronic acidderivative R²—B(OH)₂ and R²—B(OR′)₂, wherein R² and R′ are defined ashereinbefore; under transition metal catalysis yielding the product ofthe formula I.1.